Natural antihyperlipidemic agents: Current status and future perspectives

Phytopharmacology 2013, 4(3), 492-531 Ibrahim et al.

© 2013 Inforesights Publishing UK 492

Natural antihyperlipidemic agents: Current status and future perspectives Sabrin R. M. Ibrahim1,*, Gamal A. Mohamed2,3 , Zainy M. Banjar4, Hani K. M. Kamal5

1Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut, 71526 Egypt. 2Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia. 3Pharmacognosy Department, Faculty of Pharmacy, Al-Azhar University, Assiut branch, Assiut 71524, Egypt. 4Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia. 5Biomedical Engineering, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

*Corresponding author: [email protected]; Tel: +2-088-2411330; Fax: +2-088-2332776

Received: 12 January 2012, Revised: 14 March 2013, Accepted: 26 March 2013

Abstract The use of herbal or natural medicines for the treatment of various disorders has a long and extensive history. Many of these herbal medicines are finding their way onto the world market as alternatives to prescribed drugs currently available to treat various disorders/ailments. Hyperlipidemia contributes significantly in the manife-station and development of atherosclerosis and coronary heart disease (CHD). Hyperlipidemia prevalence continued to increase annually, requiring the develop-ment of drugs capable of lowering blood lipids to reduce mortality and morbidity due to cardiovascular complications. Although synthetic lipid-lowering drugs are useful in treating hyperlipidemia, there are number of adverse effects. So, the cur-rent interest has stimulated the search for new lipid-lowering agents with minimal side effects from natural sources. The purpose of this review is to highlight the cur-rent antihyperlipidemic drugs and their targets, the natural hypolipidemic agents and their mechanisms of action as well as experimental models of assessments. Keywords: Hyperlipidemia, antihyperlipidemic drugs, hypolipidemic, natural med-icines, models, assessments

1. Hyperlipidemia

Hyperlipidemia is a common disorder in developed countries. It results from abnorm-

alities in lipid metabolism or plasma lipid transport or a disorder in the synthesis and degra-dation of plasma lipoproteins resulted in high level of fat in blood (Ducharme et al 2008; Jac-obson 1998; Mungall et al 2003). It may manifest with the elevation of serum total choles-terol (TC), low-density lipoprotein (LDL), triglyceride (TG) concentrations, and a decrease



in the high-density lipoprotein (HDL) concentration (Grundy et al 1999; Ahmed et al 1998; Mahmood et al 2009). It may be responsible for oxidative modification of LDL, protein glyc-ation, glucose-autooxidation with excess production of free radicals and lipid peroxidation products (Yang et al 2008), which represent major risk factors for ischemic heart diseases (Vandewoude et al 1987). 1.1. Causes and classification

Hyperlipidemia may basically be classified as either familial (also called primary

hyperlipidemia) caused by specific genetic abnormalities, or acquired (also called secondary) when resulting from another underlying disorder that leads to alterations in plasma lipid and lipoprotein metabolism (Chait et al 1990). Primary hyperlipidemia may result from defects in the hepatic uptake and degradation of LDL via the LDLR pathway, commonly caused by mutation in the LDLR gene or in the gene encoding apoB. The most recent gene in which defects cause hyperlipidemia, is the gene encoding a member of the proprotein convertase family, PCSK9. Mutations in PCSK9 associated with hypercholesterolemia. PCSK9 norma-lly down regulates the LDLR pathway by causing degradation of LDLR protein and mutat-ions in PCSK9 result in low plasma LDL levels (Soutar et al 2007). Also, hyperlipidemia may be idiopathic without known cause. The most common causes are lifestyle habits or treatable medical conditions. Lifestyle habits include obesity, no physical activity, high dietary fat intakes, and smoking. Medical diseases that may lead to hyperlipidemia are diab-etes, kidney disease, pregnancy, and hypothyroidism (Ahmed et al 1998). One has a greater chance of developing hyperlipidemia is old aged a man ( 45years) or a woman ( 55), heart diseases or familial history of hyperlipidemia. Table 1 shows the common causes of second-dary hyperlipidemia.

Table 1. Selected causes of secondary hyperlipidemia.

Lipid Abnormality Causes

↑ LDL-C level ↑ TG level HDL-C level

Diabetes mellitus Hypothyroidism Nephrotic syndrome Obstructive liver disease Obesity or Overweight Renal insufficiency Menopause Puberty (in males) Uremia Anabolic steroids use Transplant (bone marrow, heart, kidney, or liver) Progestins Beta-adrenergic blockers Thiazides Bile acid-binding resins Estrogens Ticlopidine (Ticlid) Alcoholism Cigarette smoking



1.2. Lipids The term lipids describe an entire class of fats and fat-like substances in the blood.

The most important lipids in the blood are fatty acids, cholesterol, cholesterol esters, TGs, and phospholipids. 1.2.1. Fatty acids are identified as esters of a long-chain monobasic organic acid, which are derived from fats by hydrolysis. 1.2.2. Phospholipids (PL) are similar to the TGs but with one fatty acid residue replaced by phosphate and a nitrogenous base. 1.2.3. Triglycerides (TGs) are esters consisting of a glycerol molecule coupled to three fatty acid residues of varying carbon chain lengths and degrees of unsaturation. TGs are found in dietary fats, and can also be synthesized in the liver and adipose tissue to provide a source of stored energy. They can be mobilized when required, for example, during starvation. TGs containing both saturated and unsaturated fatty acids are important components of cell membranes (Marshall 1992). They are found in all plasma lipoproteins but are the major component of those lipoproteins with density less than 1.019 kg/L (Rosenson et al 2001). They are atherogenic because they are rich in apo C-III, which delays the lipolysis of VLDL and inhibits its uptake and clearance from plasma. 1.2.4. Cholesterol and cholesterol esters are essential elements contained in all human cell membranes. Cholesterol is a structural component of steroid hormones and bile acids. It is present in dietary fats and can also be synthesized in many tissues, including liver. It is transported in the blood as part of large molecules called lipoproteins (Marshall 1992). It works to build and repair cells, produces hormones such as estrogen and testosterone, and bile acids proven to aid in the digestion of fats (Aminoff 2004). However, the high levels of cholesterol in the blood can cause clogging, which in turn raises the risk for heart disease and/or stroke. Cholesterol along with some other types of fats cannot be dissolved in the blood. Thus in order to be transported to and from the cells, they have to be specially carried by molecules called ``lipoproteins``. 1.3. Lipoproteins

They are macromolecular complexes that carry hydrophilic plasma lipids. They are

spherical particles made up of hundreds of lipid and protein molecules. The major lipids of the lipoproteins are cholesterol, TGs, and phospholipids. Five major lipoproteins exist, each with a different function: chylomicrons, VLDLs, IDLs, LDLs, and HDLs (Marshall 1992). Apolipoproteins or apoproteins are the protein components of the lipoprotein. They also serve to activate enzymes important in lipoprotein metabolism and to mediate the binding of lipoproteins to cell surface receptors. Defects in apolipoprotein metabolism lead to abnorm-alities in lipid handling (Rader et al 1994). Classes of lipoproteins

Various types of lipoproteins are involved biochemical functions (Champe et al 2005;

Marshall 1992; Aminoff 2004; Ginsberg et al 2001):



1.3.1. Chylomicrons Chylomicrons are very large particles. They are synthesized from the fatty acids of

dietary TGs and cholesterol absorbed from the small intestine by epithelial cells for carrying new fat to the body’s cells. They carry exogenous lipids to liver, adipose, cardiac, and skel-etal muscle tissues where their TG components are released by LPL. Consequently, chylo-micron remnants are left behind which are taken up by the liver. 1.3.2. Very Low Density Lipoproteins (VLDL)

VLDLs are produced in the liver when TGs production is stimulated by an increased

flux of FFAs or by increased de novo synthesis of fatty acids by the liver. VLDL has endog-enous TGs and to a lesser degree, cholesterol. 1.3.3. Low Density Lipoproteins (LDL)

LDLs are made by the liver to transport cholesterol to the body’s cells and tissues.

LDL may form deposits on the walls of arteries and other blood vessels. Therefore they are considered as the lazy or bad cholesterol. The main benefits of lowering LDL-C include (Aminoff et al 2004; Champe et al 2005):

o Decreases the chance of heart attack and/or stroke. o Reduces the formation of new cholesterol plaques. o Eliminates existing plaques. o Prevents the rupture of existing plaques.

1.3.4. Intermediate density lipoproteins (IDL)

IDLs are formed as TGs are removed from VLDLs. The fate of IDLs is either conve-

rsion to LDLs or direct uptake by the liver. The liver takes up IDLs after they have interacted with the LDLR to form a complex, which is endocytosed by the cell. 1.3.5. High Density Lipoproteins (HDL)

HDLs pick up and transport excess cholesterol from the walls of arteries and bring it

back to the liver for processing and removal. Therefore, they are called the healthy or good cholesterol (Aminoff et al 2004; Champe et al 2005; Ducharme et al 2008). HDL also carries cholesterol esters. Table 2 shows the classification of lipoprotein, TGs, and total cholesterol levels in adults. Table 2. Classification of lipoprotein, TGs, and total cholesterol levels in adults.

Serum lipid concentration (mg/dL) Classification Comments aLDL-C 100 Optimal 100-129 Near or above optimal 130-159 Borderline high 160-189 High 190 Very high

*LDL-C is a more accurate predictor of CHD than TC. Higher LDL-C concentrations are associated with an increased incidence of CHD.



Total cholesterol (TC) 200 Desirable 200-239 Borderline high 240 High

An elevated TC level is associated with an increased risk for CHD.

bHDL-C 40 Low 60 High

*It has antiatherogenic properties that include; 1-Reverse cholesterol transport. 2-Maintenance of endothelial function. 3-Protection against thrombosis. 4-Maintenance of low blood viscosity through a permissive action on red cell deformability

TGs 150 Normal 150-199 Borderline high 200-499 High 500 Very high

1.4. Digestion and absorption of lipids The digestion of lipids begins in the oral cavity through exposure to lingual lipases,

which are secreted by glands in the tongue. Both lingual and gastric continue digestion in the stomach. The emulsification of dietary fat and fat-soluble vitamins, with peristalsis a major contributing factor takes place in the stomach. Crude emulsions of lipids enter the duodenum and then mix with bile and pancreatic juice to undergo marked changes in chemical and physical forms. In the duodenum, emulsification continues along with hydrolysis and micellization in preparation for absorption across the intestinal wall (Phan et al 2001). Pancreatic lipase, bile salts, and colipase function cooperatively to ensure the efficiency of lipid digestion and absorption. The importance of bile is indicated by the decreased rate of lipid absorption in humans with bile fistulas. Elevated concentrations of bile salts have been shown to inhibit pancreatic lipase activity in the duodenum (Verger 1984). However, colipase has been shown in vitro to restore pancreatic lipase activity (Lowe 2002). Colipase plays a critical, but not essential role in the digestion of dietary lipids by pancreatic lipases (D’Agostino et al 2002). 1.4.1. Digestion and absorption of TGs

TG is digested primarily by pancreatic lipase in the upper part of the jejunum. The

activity of pancreatic lipase on the sn-1 and sn-3 positions of the TAG molecule results in the release of 2-monoacylglycerol (2-MAG) and free fatty acids (FFAs). 2-MAG is the predominant form in which MAG is absorbed from the small intestine. The formation of 2-MAG and 1-MAG through isomerization in an aqueous medium occurs more slowly than the uptake of 2-MAG from the small intestine. Pancreatic lipase hydrolyzes of 1- or 2-MAG to glycerol and FFAs. Cholesterol esterase can also hydrolyze the acyl group at the sn-2 position to form glycerol and FFAs (Lombardo et al 1980). FFAs are taken up from the intestinal lumen into the enterocytes and used for the biosynthesis of neutral fats. 1.4.2. Digestion and absorption of phospholipids (PL)

The predominant PL in the lumen of the small intestine is phosphocholesterol (PC). It

is found in mixed micelles that contain cholesterol and bile salts. The digestion of PLs is carried out primarily by pancreatic phospholipase A2 (pPLA2) and other lipases secreted by the pancreas in response to food intake. These lipases interact with PLs at the sn-2 position to



yield FFAs and lysophosphatidylcholine. These products of lipolysis are removed from the water-oil interface when they are incorporated into the mixed micelles that form spontaneo-usly when they interact with bile salts. PLA2 deficiency has a greater effect on the digestion of TG than that of PL hydrolysis (Huggins et al 2002). It does not affect PL hydrolysis and absorption, possibly because its activity is compensated by other PLA2 enzymes (Richmond et al 2001). 1.4.3. Digestion and absorption of cholesterol

Cholesterol in the body represents both endogenous (produced in the liver and

peripheral tissues) and dietary sources absorbed from the intestine (van Heek et al 2000). Only non esterified cholesterol can be incorporated into bile acid micelles and absorbed by enterocytes. Most dietary cholesterol exists in the form of the free sterol, with only 10-15% existing as the cholesteryl ester. The latter must be hydrolyzed by cholesterol esterase to release free cholesterol for absorption. Cholesterol enters bile salt micelles prior to abso-rption. These micelles are transported to the brush border of the enterocyte, where cholesterol is absorbed. Its absorption depends on the presence of bile acids in the intestinal lumen (Voshol et al 2001) and correlates directly with the total bile acid pool. Bile salt micelles facilitate the transfer of cholesterol across the unstirred water layer. Cholesterol absorption had long been considered an energy-independent, simple, passive diffusion process. Howe-ver, it is taken up by the enterocyte with relatively high efficiency compared with structurally similar phytosterols (Moreau et al 2002). 1.5. Metabolism of lipid

There are three main pathways responsible for the metabolism and transport of lipids

within the body: exogenous, endogenous, and reverse cholesterol transport. 1.5.1. Exogenous pathway

After digestion and absorption of dietary fat, FFAs combine with glycerol to form

TGs, and cholesterol is esterified by cholesterol acyl transferase (ACAT) to form cholesterol esters. TGs and cholesterol are assembled intracellularly as chylomicrons. In the blood, circ-ulating chylomicrons interact at the capillaries of adipose tissue and muscle cells, releasing TGs to the adipose tissue to be stored and available for the body’s energy needs. LPL hydrolyzes the TGs, and FFAs are released. Some of the components of the chylomicrons are ‘‘repackaged’’ into other lipoproteins; for example, some apolipoproteins are transferred to HDL. The remaining chylomicron remnant particles are removed from the plasma by way of chylomicron remnant receptors present on the liver (Figure 1).

1.5.2. Endogenous pathway

The endogenous pathway involves the liver-synthesizing lipoproteins. TGs and chole-

sterol esters are generated by the liver. They are packaged into VLDL particles, and released into the circulation. VLDL is then hydrolyzed by LPL in tissues to release fatty acids and glycerol becomes a VLDL remnant. The fatty acids are taken up by muscle cells for energy or by adipose cells for storage. VLDL remnants are taken up by the liver by



Figure 1. The exogenous pathway (LPL, lipoprotein lipase; FFA, free fatty acids; CM, chylomicron; CM-REM, chylomicron remnant; REM, remnant receptor; CH, cholesterol.) LDLR. The remaining remnant particles become IDL, which are reabsorbed by the liver thro-ugh the LDLR. Others are hydrolyzed in the liver by HL to form LDL. It is used by extrah-epatic cells for cell membrane and steroid hormone synthesis. Most LDL particles are taken up by LDLR in the liver. The remaining particles are removed by way of scavenger pathways at the cellular level. LDLR activity and uptake regulates plasma LDL concentration through several mechanisms, including decreasing the synthesis of 3-hydroxy-3-methylglutaryl coen-zyme A (HMG-CoA) reductase, which controls the rate of de novo cholesterol synthesis by the cell. This process suppresses the synthesis of new LDLR in the cells and activates the enzyme ACAT, which esterifies free cholesterol into cholesterol ester, storing cholesterol in the cell (Figure 2). 1.5.3. Reverse cholesterol transport

Cholesterol is removed from the tissues and returned to the liver through reverse cho-

lesterol transport process. HDL is the key lipoprotein involved in reverse cholesterol trans-port and the transfer of cholesteryl esters between lipoproteins. It is formed through a matur-ation process whereby precursor particles (nascent HDL) secreted by the liver and intestine proceed through a series of conversions known as the HDL cycle to attract cholesterol from cell membranes and free cholesterol to the core of the HDL particle. Several mechanisms have been suggested, including the action of cholesteryl ester transfer protein (CETP), which transforms HDL into a TG-rich particle that interacts with hepatic triglyceride lipase. Chole-



Fig. 2. The endogenous pathway. LPL, lipoprotein lipase; FFA, free fatty acids; VLDL, very low density lipop-roteins; IDL, intermediate-density lipoproteins; LDL, low density lipoproteins; LDLR, low density lipoproteins receptor; CH, cholesterol; TGs, triglycerides. sterol ester-rich HDL may also be taken up directly by the receptors in the liver. Another me-chanism may be that cholesterol esters are delivered directly to the liver for uptake without catabolism of the HDL-C particle. The net effect is the removal of excess cholesterol from cells, which constitutes most of the antiatherogenic effect of HDL. All nucleated cells synth-esize cholesterol but only hepatocytes can efficiently metabolize and excrete cholesterol from the body. The predominant route of cholesterol elimination is by excretion into the bile, eit-her directly or after conversion to bile acids. Cholesterol in peripheral cells is transported fr-om the plasma membranes of peripheral cells to the liver by an HDL-mediated process termed reverse cholesterol transport (Figure 3). 1.6. Hyperlipidemia associated diseases 1.6.1. Hyperlipidemia and atherosclerosis

The relationship between cholesterol and atherosclerosis has been known for a long

time. Diabetes and metabolic syndrome are often accompanied by hypertriglyceridemia and related to atherosclerosis. Although there is no doubt that hypertriglyceridemia and atherosc-lerosis are closely related. Mechanisms of increased atherogenecity are believed to be related to two effects endothelial dysfunction which is independent of the concentration of lipopro-teins and direct effect of lipoproteins. The direct effect includes enhanced oxidative suscep-tibility (Chait et al 1993; Galeano et al 1998) and reduced clearance by LDLR in the liver with increased LDLR-independent binding in the arterial wall (Slyper 1994; Selby et al 1993). Small dense LDL is indirectly associated with atherogenic risk through its inverse



Fig. 2. HDL cycle and reverse cholesterol transport. CETP, cholesteryl ester transfer protein; VLDL, very low density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; HDL, high-density lipoproteins; LDLR, low-density lipoprotein receptor; TGs, triglycerides; SR-B1, scavenger receptor class B1, cholesterol; CH. relationship with HDL-C, functions as a marker for accumulation of atherogenic TG remnant particles, and plays a role in insulin resistance (Ross 1993). LDL-C promotes inflammatory and immune changes through cytokine release from macrophages and antibody production. Release of cytokines stimulates smooth muscle proliferation. Thus, foam cell and platelet accumulation and smooth muscle proliferation contribute to the formation of an atheros-clerotic plaque. 1.6.2. Hyperlipidemia and obesity

Obesity is frequently accompanied by hyperlipidemia. The increase in adipocyte mass

and accompanying decrease in insulin sensitivity associated with obesity have multiple eff-ects on lipid metabolism. More FFAs are delivered from the expanded adipose tissue to the liver where they are re-esterified in hepatocytes to form TGs. They are packaged into VLDL for secretion into the circulation. Plasma HDL-C tends to be low in obesity. Weight loss is often associated with a reduction of plasma apoB-containing lipoproteins and an incr-ease of plasma HDL-C (Ahmed et al 2009; Charlton 2009). The changes in lipid metabolism acco-mpanied with abdominal fat accumulation include hypertriglyceridemia, reduced HDL-C, and increased LDL particles. The hypertriglyceridemia seen with obesity and insulin resis-tance is related to the over secretion of TG-rich VLDL particles. An increased rate of hepatic FFAs uptake stimulates the secretion of apoB-100, leading to increased numbers of apoB-containing particles and possibly hypertriglyceridemia (Marsh 2003). VLDL particles are exposed to LPL in the peripheral circulation. LPL hydrolyzes the TGs in VLDL particles to generate FFA. These FFAs are taken up by muscle and adipose tissue for energy use or storage. The resultant remnant particles are then processed by the liver to form LDL. An increased number of small dense LDL particles is a constant feature of the dyslipidemia of abdominal adiposity. They are associated with insulin resistance, intraabdominal fat, and hy-



pertension (Mc Namara et al 1987; Swinkels et al 1989; Austin et al 1990). The presence of small dense cholesterol-depleted LDL particles is associated with an increased risk of myoc-ardial infarction (Austin et al 1988; Stampfer et al 1996; Lamarche et al 1997) and worsened severity of CAD (Tornvall et al 1991; Campos et al 1992; Gardner et al 1996).

1.6.3. Hyperlipidemia and diabetes mellitus

Patients with type 1 diabetes mellitus are generally not hyperlipidemic if they are un-

der good glycemic control. Diabetic ketoacidosis is frequently accompanied by hypertri-glyc-eridemia due to increased hepatic influx of FFAs from adipose tissue. Type 2 diabetes is frequently associated with elevations of plasma LDL-C and TGs, and reduced levels of HDL-C (Vinik et al 1993; Manzato et al 1993). The high levels of insulin and insulin resistance associated with type 2 diabetes have multiple effects on fat metabolism (Vinik et al 1993; Manzato et al 1993). In some diabetic patients, especially those with a genetic defect in lipid metabolism, TGs can be extremely elevated. Elevated plasma LDL-C levels are usually not a feature of diabetes mellitus and suggest the presence of an underlying lipoprotein abnorma-lity or may indicate the development of diabetic nephropathy (Consensus Statement 1993).

1.6.4. Hyperlipidemia and renal disorders

Progressive renal failure especially that associated with proteinuria is accompanied by

abnormalities of lipoprotein transport. In proteinuric patients, cholesterol levels may be very high (Vaziri et al 2003). These abnormalities are due to several pathogenetic mechanisms. Urinary protein loss stimulates an increased LDL synthesis by the liver. Hypoalbuminemia as a result of proteinuria leads to an upregulation of HMG-CoA reductase with a consequent hypercholesterolemia (Vaziri et al 2003). Conversely, low HDL with a poor maturation of HDL-3 to cholesterol-rich HDL-2 is due to acquired LCAT deficiency secondary to abnormal urinary losses of this enzyme (Vaziri et al 2001). Impaired clearance of chylom-icrons and VLDL has emerged as the dominant factor for the increased serum TG concen-tration. LPL is the rate limiting step in lipolysis of chylomicrons and VLDL. A downer-gulation of LPL protein abundance and enzymatic activity was found in proteinuric renal diseases (Vaziri et al 2003). All these are responsible for the abnormalities in lipoprotein metabolism in nephrotic syndrome and chronic renal failure’s rendering these lipoproteins more atherogenic. The abnormal serum lipid levels may contribute to renal disease progre-ssion. These lipids bind to and become trapped by extracellular matrix molecules (Abrass 2004). Where, they undergo oxidation increasing the formation of reactive oxygen species (ROS) such as superoxide anion and hydrogen peroxide (Chait et al 1994). The reduction in the actions of endothelium-derived vasodilators/growth inhibitors, such as prostacyclin and nitric oxide, with maintenance or increased formation of endothelium-derived vasocons-trictors/growth promoters, such as angiotensin II, endothelin-1, and plasminogen activator inhibitor-1, has significant vascular and renal pathophysiologic consequences. Macrophages phagocytize oxidized lipids and undergo a transition to foam cells. Macrophage-derived foam cells release cytokines that recruit more macrophages to the lesion and influence lipid deposition, endothelial cell function, and vascular smooth muscle cell proliferation. Glomer-ular cells mimic some of these characteristics of cells in the atherosclerotic vessel wall (Wh-eeler et al 1993).



1.6.5. Hyperlipidemia and liver disorders Liver is the principal site of formation and clearance of lipoproteins. The liver dise-

ases can profoundly affect plasma lipid levels in a variety of ways. Hepatitis due to infection, drugs, or alcohol is often associated with increased VLDL synthesis and mild to moderate hypertriglyceridemia. Severe hepatitis and liver failure are associated with dramatic reduce-tions in plasma cholesterol and TGs due to reduced lipoprotein biosynthetic capacity (Yang 2004). Cholestasis is associated with hypercholesterolemia, which sometimes can be very severe. The major pathway by which cholesterol is excreted is via secretion into bile, either directly or after conversion to bile acids. Cholestasis blocks this critical excretory pathway. In cholestasis, free cholesterol coupled with PLs are secreted into the plasma as constituents of a lamellar particle called Lp(X).These particles can deposit in skin folds, producing lesi-ons resembling those seen in patients with FDBL (familial dysbetalipoproteinemia) (Yang 2004).

1.6.6. Hyperlipidemia and thyroid diseases

Hypothyroidism is associated with elevated plasma LDL-C due primarily to a reduce-

tion in hepatic LDLR function and delayed clearance of LDL. Plasma LDL-C is often reduced in the hyperthyroid patient. Hypothyroid patients may have increased circulating IDL, and some are mildly hypertriglyceridemic. Thyroid dysfunction leads to changes in lip-oprotein metabolism. Plasma LDL-C and HDL-C levels increase in hypothyroidism and decrease in hyperthyroidism (Heimberg et al 1985; Muls et al 1982; Muls et al 1984). Fur-thermore, clearance of chylomicron remnants is decreased in hypothyroidism (Weintraub et al 1999). Changes in LDL-C are mainly attributable to altered clearance of LDL-C from plasma by changes in the number of LDLRs on liver cell surfaces (Song et al 1990). Because the promoter of the LDLR gene contains a thyroid hormone responsive element (TRE), T3 could modulate gene expression of the LDLRs (Bakker et al 1998). HDL-C metabolism is complex, and changes in plasma levels are due to remodeling of HDL-C particles by HL and CETP (Tall 1993). Activity of both enzymes decreases in hypothyroidism and increases in hyperthyroidism, correlating with plasma HDL-C (Dullaart et al 1990; Ritter et al 1996; Tan et al 1998). The extent of these changes depends both on the severity and duration of thyroid dysfunction and on the degree of pretreatment hypercholesterolemia (Kung et 1995; Tanis et al 1996; Verdugo et al 1987).

1.6.7. Hyperlipidemia and Cushing`s syndrome

Glucocorticoid excess is associated with increased VLDL synthesis and hypertrigly-

ceridemia. Patients with Cushing`s syndrome can also have mild elevations in plasma LDL-C. The hyperlipidemia seen in patients who have Cushing’s syndrome appears to be similar to the dyslipidemia associated with the metabolic syndrome. There is an increase in VLDL and LDL with a decrease in HDL levels. This results in elevation of total TGs and cholesterol levels (Taskinen et al 1983; Friedman et al 1996).

1.6.8. Hepatic lipase (HL) deficiency

HL is a member of the same gene family as LPL and hydrolyzes TGs and PLs in rem-

nant lipoproteins and HDL. HL deficiency is a very rare autosomal recessive disorder chara-



cterized by elevated plasma cholesterol and TGs (mixed hyperlipidemia) due to the accumu-lation of lipoprotein remnants. HDL-C is normal or elevated. The diagnosis is confirmed by measuring HL activity in post-heparin plasma. Due to the small number of patients with HL deficiency, the association of this genetic defect with ASCVD is not known, but lipid-lower-ing therapy is recommended.

1.6.9. Glycogen storage diseases

Other rarer causes of secondary hyperlipidemia include glycogen storage diseases su-

ch as von Gierke’s disease. It is caused by mutations in glucose-6-phosphatase. The inability to mobilize hepatic glucose during fasting results in hypoinsulinemia and increased release of FFAs from adipose tissue. Hepatic fatty acids synthesis is also increased, resulting in fat accumulation in the liver and increased VLDL secretion. The hyperlipidemia associated with this disease can be very severe but responds well to treatment of the underlying disorder. 1.7. Symptoms and diagnoses of hyperlipidemia

Hyperlipidemia in general has no apparent symptoms. It is discovered and diagnosed

during routine examination or evaluation for ASCVD. However, deposits of cholesterol may be formed under the skin in individuals with familial forms of the disorder or in persons with very high levels of cholesterol in the blood. In individuals with hypertriglyceridemia, several pimple-like lesions may be developed across their bodies. Pancreatitis, a severe inflammation of the pancreas that may be life-threatening can also be developed due to extremely high levels of TGs. For diagnosis of hyperlipidemia, levels of TC, LDL-C, HDL-C, and TGs are measured in a blood sample. It is important to note that the lipid profile should be measured in all adults 20 years and older. The measurement should be repeated after every 5 years. Food or beverages may increase TG levels temporarily, so people must fast at least 12 hours before giving their blood samples. Special blood tests are carried out to identify the specific disorder when lipid levels in the blood are very high. Specific disorders may include several hereditary disorders, which produce different lipid abnormalities and have different risks. 1.8. In vitro and in vivo experimental models of antihyperlipidemic assessments

The most commonly used models for antihyperlipidemic assessments are listed below in table 8. Table 3. The list of experimental models for antihyperlipidemic assessments.

Model name Uses Comments

Larval zebrafish Investigate dietary plant-based intervention of the pathophysiology of hypercholesterolemia.

1- Zebrafish digestive physiology and lipid metabolism are very similar to that of humans

2- Treatment of zebrafish with antihyperlipidemic drugs elicits similar responses to their mammalian counterparts (Carten et al 2009; Stoletov et al 2009).

3- Zebrafish exhibit similarities to human lipid-related pathologies including increased vascular permeability and thickening, increased levels of TC, LDL, and oxidized cholesteryl esters (Hama et al 2009; Fang et al 2010).

4- Blood serum lipid levels in adult zebrafish can be reduced by treatment with herbal extracts (Jin et al 2011).



Triton WR-1339 Used to produce acute hyperlipidemia in animal models in order to screen natural or chemical drugs (Schurr et al 1972) and to study cholesterol and TG metabolism (Zeniya et al 1988).

1- Triton is a non-ionic detergent (oxyethylated tertiary octyl phenol formaldehyde polymer).

2- The accumulation of plasma lipids by this detergent appears to be especially due to the inhibition of LPL activity (Hayashi et al 1981).

3- It has been widely used to block clearance of TG-rich lipoproteins to induce acute hyperlipidemia in several animals (Srinath et al 2011).

4- It was dissolved in normal saline (pH 7.4) and administered intraperitoneally to the rat (200 mg/kg B.W.) in order to develop an acute hyperlipidemia.

Poloxamer 407

Screening of hypolipidemia property of the drugs.

1- P 407-induced hypercholesterolaemia is associated with alterations in activity of HMG-CoA reductase, LPL, LCAT, CETP, and HL (Johnston et al 1997).

2- It directly inhibits the heparin-relaseable fraction of LPL and HL. 3- It indirectly increases the biologic activity of CETP and LCAT

(Johnston 2004). 4- A single injection of P 407 has been shown to cause elevations of

serum cholesterol and TG levels in rats (Wout et al 1992). ApoE-deficient and apoE-transg-enic mice

Hyperlipidemia 1- There is a relationship between variations in the apoE gene, modu-lation of plasma lipids and lipoproteins, incidence of coronary, peri-pheral and cerebrovascular diseases.

2- ApoE is an arginine-rich glycoprotein with pleiotropic biological effects.

3- ApoE was first ascribed a role in receptor-mediated clearance of plasma lipoproteins.

4- It was synthesized by various peripheral cells such as macrophages and astrocytes (Mahley 1988; Mazzone 1996).

5- Hyperlipidemia of apoE deficient mice fed regular chow is charac-terized by hypercholesterolemia without hypertriglycerid-emia.

6- Cholesterol levels are similar to those found in humans with familial hypercholesterolemia.

7- However, feeding these mice with high fat diets dramatically incre-ases not only plasma cholesterol but also TG levels, thereby mimi-cking type III familial hyperlipoproteinemia (Plump et al 1992; Ghiselli et al 1982).

8- Transgenic mice expressing mutant forms of apoE known as apoE-Cys142 and apoE Leiden develop mild hyperlipidemia on a chow diet, and severe hypercholesterolemia and fatty streak lesions in response to a high-cholesterol and high-fat diet (Fazio et al 1994).

LDLR-deficient mice

Study the accelerating effect of hyperglycemia on atherosclerosis in a mouse model.

1- Hyperglycemia was induced by using intraperitoneal streptozotocin (STZ) in LDLR-deficient (LDLR-D) mice fed a high-fat high-cholesterol diet.

2- LDLR-D mice faced with the double challenge of STZ-induced hyperglycemia and diet-induced hyperlipidemia develop atheroscle-rotic lesions that exceed those induced by a high-fat diet alone.

3- The advantage of this model is that both risk factors are induced exogeneously (hyperglycemia by STZ and hyperlipidemia by high-fat diet feeding) (Reaven et al 1997).

Caco-2 human intestinal cells

Study the characteristics and regulation of proce-sses associated with the apical uptake, metabolism, and trans epithelial transp-ort of diverse nutrients and other dietary components includes amino acids, cho-lesterol, fatty acids, mono-saccharides, nucleosides, calcium, iron, and bioac-tive polyphenols (Delie et al 1997).

1- Caco-2 is a cell line originating from human colonic carcinoma that exhibits some morphological and functional characteristics similar to those of differentiated epithelial cells that line the intestinal mucosa (Sambruy et al 2001).

2- The biochemical characteristics of differentiated Caco-2 cells are similar to those of normal small intestinal enterocytes.

3- Caco-2 cells use the glycerol 3-phosphate pathway for the synthesis of TGs.

C57BL/6 mouse Study the relation between hyperlipidemia and atherosclerosis.

1- Certain inbred strains of mice could develop atherosclerotic lesions in response to diets high in cholesterol and fat, and which contained cholic acid to block cholesterol conversion to bile acids.



2- The C57BL/6 diet-induced model of atherosclerosis has proven useful in the examination of the effects of expression of various candidate genes on susceptibility to atherosclerosis (Smith 1998; Fazio et al 1997).

3- It is used as control system in the analysis of atherosclerosis attenuation or potentiation by different interventions in engineered mice (Smith 1998; Fazio et al 1997).

ApoB-mice Study the role of apoB-100 in lipid metabolism and atherogenesis (Callow et al 1994; Chiesa et al 1993).

1- The transgenic mice have a plasma lipoprotein profile which more closely parallels that of humans, including a distinct LDL-C peak.

2- On a normal chow diet, the mice have mild hypercholesterolemia and hypertriglyceridemia.

3- In a high-fat, high-cholesterol diet containing cholic acid, the mice developed severe hypercholesterolemia with cholesterol levels >300 mg/dL due to the presence of a cholesterol ester enriched VLDL and LDL (Purcell-Huynh et al 1995).

4- The human apoB transgene have been bred onto the background of LDLR deficiency (Sanan et al 1998).

1.9. Current antihyperlipidemic drugs Several different classes of drugs are used to treat hyperlipidemia (Table 3-7). These

classes differ not only in their mechanism of action but also in the type of lipid reduction and the magnitude of the reduction. The followings are the commonly used group of drugs to treat hyperlipidemia; Table 4. Statins.

Mechanism of action Examples Side effects

Drugs of the statin class are structu-rally similar to A HMG-CoA, which is the precursor of cholesterol. They are competitive inhibitors of HMG-CoA reductase, the last regulated step in the synthesis of cholesterol (Hort-on et al 2002).

1- Simvastatin and atorvastatin 80 mg/day. 2- Rosuvastatin 40 mg/day (Hunninghake et al 2004).

Myopathy, hepatitis, renal insuffic-iency, hypothyroidism, loss of con-centration, sleep disturbance, and headache.

Table 5. Bile-acid sequestrants.


Resins bind bile acids (not cholesterol) in the inte-stine, the bile-acid sequestrants are highly positi-vely charged resins and bind negatively charged bile acids. Because of their large size, they are not absorbed. The bound bile acids are excreted in the stool. Thereby interrupting the enterohepatic circ-ulation of bile acids and increasing the conversion of cholesterol into bile acids in the liver. Hepatic synthesis of cholesterol is also increased, which in turn increases the secretion of VLDL into the circulation, raises serum TG concentrations, and limits the effect of the drug on LDL cholesterol concentrations (Shepherd et al 1980).

1- Cholestyramine 8-12 g. 2- Colestipol 10-15 g. *The doses given with meals as a suspension in juice or water.

1- Bloating and dyspepsia (Davi-dson et al 1999).

2- Cholestyramine and colestipol bind and interfere with the ab-sorption of many drugs, inclu-ding some thiazides, furosem-ide, propranolol, digoxin, and warfarin (Farmer et al 1994).

Table 6. Niacin (Nicotinic Acid).




Niacin inhibits the mobilization of FFAs from peripheral tissues, thereby reducing hepatic synthesis of TGs and secretion of VLDL. It also inhibits the conversion of VLDL into LDL (Jin et al 1999).

Crystalline niacin tablets (NIASPAN) 1- Flushing and dyspepsia. 2- Purities of the face and upper

trunk, and skin rashes which are prostaglandin-mediated (Stern et al 2000).

3- Hepatotoxicity.

Table 7. Fibric acid derivatives (PPAR activators).


These drugs acted by their interaction with PPARs (Kersten et al 2000), which regulate gene transcription. Fibrates bind to PPARα, which is expressed primarily in the liver and brown adipose. Clofibrate and related drugs resemble, in part, short-chain fatty acids and increase the oxidation of fatty acids in both liver and muscle as well as decreased secretion of TG-rich lipoproteins. In muscle, the incr-ease in fatty-acid oxidation is associ-ated with an increase in both LPL activity and the uptake of fatty acids.

1- Gemfibrozil (LOPID) 600 mg twice a day. 2- Fenofibrate (TRICOR) 145 mg. 3- Fenofibrate (LOFIBRA) 67, 134, and 200 mg. 4- TRICOR 145 mg and LOFIBRA 200 mg.

1- Gastrointestinal side effects occur in up to 5% of patients.

2- Rash, urticaria, hair loss, myalgias, fatigue, headache, impotence, and anemia.

3- Clofibrate, bezafibrate, and fenofib-rate have been reported to poten-tiate the action of oral anticoag-ulants, in part by displacing them from their binding sites on albumin.

Table 8. Ezetimibe and the inhibition of dietary cholesterol uptake.


Ezetimibe is glucuronidated rapidly in the intestines, and once it is glucuron-idated, undergoes enterohepatic recirc-ulation. The drug delivers repeatedly to its site of action by selective inhibition of the absorption of cholesterol from the intestinal lumen into enterocytes. The glucuronide of ezetimibe is much more effective than the parent drug, mainly because of its localization at the brush border of the intestines. Both ezetimibe and its glucuronide are recir-culated and delivered back to their site of action in the intestine, resulting in more efficacies. Ezetimibe also inhibits intestinal absorption of plant sterols (Sudhop et al 2002).

Ezetimibe 10 mg.

Upper respiratory tract infection, diarr-hea, arthralgia, sinusitis and pain in extre-mity

1.10. Drugs under development to regulate LDL 1.10.1. Cholesteryl ester transfer protein inhibitors (CEPT)

CETP is a plasma glycoprotein synthesized by the liver that mediates the transfer of

cholesteryl esters from the larger subfractions of HDL to TG-rich lipoproteins and LDL in exchange for a molecule of TG. Enrichment of HDL with TGs enhances its catabolism by the liver. So, inhibition of CETP results in higher HDL levels decreased LDL levels, and resist-ance to developing atherosclerosis. Two CETP inhibitors, JTT-705 and torcetrapib are being tested (Brousseau et al 2004; Clark et al 2004).



1.10.2. Squalene synthase inhibitors: potential cholesterol-lowering drugs Two classes of drugs have been developed: (I) squalene synthase inhibitors, which act

at the first committed step in cholesterol biosynthesis, distal to the mevalonate-farnesyl diph-osphate pathway; and (II) oxidosqualene cyclase inhibitors, which act distal to the squalene intermediate. Squalene synthase inhibitors decrease circulating LDL-C by the induction of hepatic LDLR in a similar manner to statins (Menys et al 2007). Examples of the inhibitors are zaragozic acid (Vaidya et al 1998), RPR107393 which inhibited de novo cholesterol biosynthesis and reduced plasma TC levels by at least 35% in rats (Amin et al 1997). As well as, YM-53601 which reduced non-HDL-C concentrations by 47% in guinea pigs and 37% in rhesus monkey (Ugawa et al 2000), and TAK-475 (Amano et al 2003). 1.10.3. Proprotein covertase subtilisin/kexin type 9 (PCSK9) inhibitors

PCSK9 is a member of the proteinase K subfamily of subtilisin-related serine endopr-

oteases. PCSK9 binds to the LDLR in the liver and accelerates its degradation, leading to elevated plasma LDL-C. The inactivation of PCSK9 in mice reduces plasma cholesterol leve-ls primarily by increasing hepatic expression of LDLR protein and thereby promoting clear-ance of circulating LDL-C. So, regulation of PCSK9-LDLR expression is becoming a novel therapeutic target for dyslipidemia (Frank-Kamenetsky et al 2008; Akram et al 2010). Berberine pretreatment reduced the expression of hepatic PCSK9, decreased the plasma TC, TG, LDL-C, IFN, TNFα, IL-1α, and 8-isoprostane concentrations; increased HDL-C level and LDLR expression in mice (Xiao et al 2012). 1.10.4. Antisense oligonucleotides apoC-III inhibitors

This drug is designed to reduce plasma levels of apoC-III, an endogenous inhibitor of

LPL activity. Knockdown of apoC-III would therefore act to potently reduce plasma TGs via increased lipolysis. In addition, apoC-III is thought to interact with the LDLR and prevent binding of on LDL. The benefit of reducing apoC-III levels would enhance binding of LDL to LDLRs, resulting in further LDL-C lowering (Davidson et al 2009). Mipomersen is a second generation antisense oligonucleotide (Stein 2009). 1.10.5. Microsomal triglyceride transfer protein inhibitors

MTP is a lipid transfer protein localized in the endoplasmic reticulum of hepatocytes

and enterocytes. It plays a critical role in lipoprotein lipidation. It is necessary for formation of chylomicrons, VLDL, and downstream remnants (Stein 2009). 1.11. Antihyperlipidemic natural products

The dissatisfaction with high costs and potentially hazardous side-effects of synthetic

hypolipidemic drugs, the potential of natural products for treating hypolipidemia is under exploration. This may be an excellent alternative strategy for developing future effective and safe hypolipidemic drugs. A variety of natural products, including crude extracts and isolated compounds from plants can reduce body cholesterol and prevent hyperlipidemia. A wealth of information indicates numerous bioactive components from nature are potentially useful in



hyperlipidemia and/or hypercholesterolemia treatments. A good example of such is the poly-phenols as apigenin, genistein, and catechins show strong antihypercholesterolemic activity. Saponin, sterols, stanols polyunsaturated fatty acids, mucilage, and carbohydrates also have potent hypocholesterolemic activity. Pancreatic lipase inhibitors

Pancreatic lipase inhibition is one of the most widely studied mechanisms for deter-

mining antihyperlipidemic activity of natural products (Birari et al 2007). Pancreatic lipase is a key enzyme in dietary TG absorption. It hydrolyzes TAG to MAG and FAs. Tetrahydro-lipstatin (orlistat) is a derivative of the naturally-occurring lipase inhibitor produced by Streptomyces toxytricini (Ballinger et al 2002). It inhbits pancreatic lipase through a covalent bond to the lipase’s active site serine (Tsujita et al 2006). A wide variety of plants possess pancreatic lipase inhibitory effects including; Panax japonicus (Han et al 2005), Platycodi radix (Han et al 2000), Salacia reticulata (Kishino et al 2006), Nelumbo nucifera (Ono et al 2006), and so on (Table 9). Many phytochemicals as saponins, polyphenols, flavonoids, carb-ohydrate and caffeine have pancreatic lipase inhibitory activity (Takao et al 2006; Moreno et al 2006; Shimoda et al 2006). The different types of teas (e.g. green, oolong, and black tea) showed strong activity against pancreatic lipase (Nakai et al 2005; Thielecke et al 2009). The following table gives examples for some natural products have pancreatic lipase inhibitory activity (Table 9). Table 9. Natural pancreatic lipase inhibitors.

Source Used part and/or active constituents

Comments

Juniperus communis (bark) Illicium religiosum (wood)

Crude EtOH/H2O extract

IC50 = 20.4 and 21.9 g/mL, respectively (Kim et al 2005).

Cassia mimosoides Proanthocyanidin IC50 = 0.11 mg/mL (Yamamoto et al 2000). Afromomum meleguetta, Spilanthes acmella

Crude H2O extract 1- 40 % and 90% lipase inhibition, respectively (Ekanem et al 2007)

2- 2 mg/mL, inhibitory activity of pancreatic lipase Vitis vinifera Crude EtOH extract 1- 80 % Inhibitory effect on lipase, (Moreno et al 2003).

2- 1 mg/mL, 3T3-L1 adipocyte, 8 days Salvia officinalis L.(leaf) MeOH extract

(carnosic acid) IC50=36 g/mL, (Ninomiya et al 2004).

Cassia nomame Flavan dimers IC50= 5.5M with (2S)-3`,4`,7`-tri-hydroxyflavan-(4α→8) – catechin, (Hatano et al 1997).

Glycyrrhiza uralensis Licochalcone A IC50 =35 g/mL (Won et al 2007). Citrus unshiu Hesperidin IC50 =32 g/mL (Kawaguchi et al 1997). Tylopilus felleus (fungus) Mycelia extract 1- 96 % inhibitory effect on lipase (Slanc et al 2004).

2- 2 mg/mL fungal extract showed inhibitory activity.

Streptomyces toxytricini Lipistatin IC50= 0.14M (Weibel et al 1987). Caulerpataxifolia (Marine algae)

Caulerpenyne IC50 = 2mM (Tomoda et al 2002).

Table 10. Natural HMG-CoA reductase inhibitors.

Source Used Part and/or active constituents Mechanism of action Comments

Cynara scolymus (Globe Artichoke leaf)

Cynaroside and its derivative luteolin. 1- In vitro lipid-lowering acti-vity through indirect inhib-ition of HMG-CoA reduce-tase (Gebhardt 1998) act-ion due to cynaroside and

1800 mg/day divid-ed into 2-3 doses (Englisch et al 2000).



its derivative luteolin. They have block HMG-CoA red-uctase similar to statins.

2- Luteolin exerted the high-est inhibitory potency and effectively blocked the stimulation of cholesterol biosynthesis by insulin (Heckers et al 1977).

Allium sativum (Garlic)

Organosulfur constituents (Garlic oil, aged garlic, fresh garlic, and garlic po-wder).

1- Its active constituents inhibit cholesterol synthe-sis by blocking enzymes such as HMG-CoA reduc-tase, squalene epoxidase, and glucose-6-phosphate dehydrogenase (Gebhardt et al 1996; Yeh et al 2001).

2-They increased catabolism of FA containing lipids es-pecially TGs (Gadkari et al 1991).

1- Garlic reduces 5-15 % of TC (Ste-vinson et al 2000).

2- Garlic extract 600 -1200 mg divid-ed and given thr-ee times daily.

Policosanols Policosanols are a mixture of alcohol usually extracted from sugar cane wax or beeswax and composed primarily of octacosanol (Gouni-Berthold et al 2002).

They are effective in the treat-ment of type II hypercho-lesterolemia through inhibi-tion of hepatic cholesterol sy-nthesis by blocking HMG-CoA reductase.

Doses of up to 20 mg/day policosanols have lowered TC and LDL-C by more than 20 % and raised HDL by up to 15 %.

Monascus purpureus (Red yeast Rice) Red yeast rice is prepared from cooked non-glutinous white rice fermented by the yeast Monascus purp-ureus, which is then sterilized, dried, grou-nded, and encapsula-ted.

Monacolin K, omega-3 fatty acids, isoflavones, sterols, and saponins (Me-Carthy 1998).

Inhibition of HMG-CoA reductase.

1- Red yeast rice is a dietary staple in many Asian cou-ntries, with typ-ical dietary cons-umption ranging from 14 to 55 g/d (Heber et al 1999).

2- 2.4 g/d red yeast rice significantly lowered cholesterol from 250 mg/dL to 208 mg/dL (17 %) (Heber et al 1999). LDL-C levels dropped from 173 to 134 (22 %), TGs dro-pped from 133 to 118 (12 %).

Ichnocarpus fruescens (Black Creeper)

Polyphenols, flavonoids, iridoid glyco-sides, sterols, and pentacyclic triterpin-oids.

Inhibits HMG-CoA reductase in liver lead to decrease chol-esterol biosynthesis (Kum-arappan et al 2007).

The dose of polyp-henolic extract of leaves of I. frutes-cens is 300 mg/kg.

Quercus infectoria. Rosa domascena Myrtus communis

Terpenes, sterols, and polyphenols. Potent HMG-CoA reductase inhibitors (Deng 2009).

Vitis vinifera (Grap-es) Actinidia arguta (kiwifruit) Anethum graveolens (Dill)

Polyphenolic contents. Potent HMG-CoA reductase inhibitors activity (Gholam-ho-seinian et al 2010; Yazd-anparast et at 2008).

Kiwifruit showed at dose 0.15 mg/mL more than 60 % inh-ibitory effect of HMG-Co A reduct-ase.

Citrus bergamia Flavonoid (hesperetin), flavonoid glyc- 1- Bergamot cause lowering



(Bergamot) osides (naringin and neohesperidin), buteridine and melitidine (3-hydroxy-3-methylglutaryl derivatives of hesper-etin and naringenin, respectively), and pectins (Mollace et al 2011).

of cholesterol levels by modulating hepatic HMG-CoA reductase levels by binding bile acids and increasing the turnover rate of blood and liver chole-sterol. It enhances the exc-retion of fecal sterols in rats. Hesperetin reduces hepatic TG accumulation and this is associated with the reduced activity of TG synthetic enzymes, such as phosphatidate phosphohydrolase.

2- Buteridine and melitidine are structural similar to HMG-CoA reductase subs-trate. They possess the sta-tin-like properties by selec-tive inhibition of HMG-CoA reductase.

Biebersteinia multifida DC

Luteolin derivatives. Luteolin derivatives are pote-nt HMG-CoA reductase inhi-bitors. They act as novel anti-hyperlipidemic agents by usi-ng the molecular docking me-thod (Nematollahi et al 2012).

The following table 11 showed % inhibition of HMG-CoA reductase by some plants

extracts (Gholamhoseinian et al 2010). Table 11: % inhibition of HMG-CoA reductase by some plants extracts.

Source Part us Part used ed

Inhibition (%)

Citrus aurantium Flowers 26.8 Cuminum cyminum Seeds 26.0 Eucalyptus galbie Leaves 43.0 Gundelia tournefortii Aerial parts 40.0 Heracleum persicum Fruits 45.4 Laurus nobilis Leaves 44.4 Lawsonia inermis Leaves 40.1 Levisticum officinale Roots 48.0 Mentha longifolia Aerial parts 44.0 Mentha piperita Leaves 37.3 Myrtus communis Leaves 62.0 Peucedanum aucheri Roots 37.0 Pimpinella anisum Seeds 10.5 Piper nigrum Fruit hull 21.0 Punica granatum Leaves 40.1 Quercus infectoria Galls 84.0 Rosa damascene Florets 70.0 Zingiber officinale Rhizomes 20.0

Table 12. Natural products decrease absorption of lipids.


Mechanism of action Comments

Plant sterols and stanols Phytosterols are structural similar to cholesterol. They impair intestinal absorption of

1- Dose 2-3 g/day. 2- Most products on the

market are esterified to



cholesterol resulting in a 10-15 % reduction in LDL-C (Wong 2001). Esterification of these sterols increases their solubility in fat and their efficacy in low-ering LDL-C (Vanhanen et al 1993).

unsaturated fatty acids (st-erol esters) or saturated fat (stanol esters).

3- Plant sterols possess a methyl or ethyl group in their side chains making them poorly absorbed.

Vegetable oils, as areca nut oil

Monounsaturated fats They reduce LDL-C, but not HDL-C (Wen-hua et al 2011).

Camellia sinensis (Tea) Polyphenolic flavonoids. 1- Polyphenolic antioxidants inhibit lipid peroxidation (Bursill et al 2001).

2- Tea increases the expression of the hepatic LDL-C recap-tor and increases the fecal excretion of bile acids and cholesterol (Yang et al 2000).

3- Green tea catechins and ga-llate esters reduce intestinsl cholesterol absorption and inhibit platelet aggregation

Curcuma longa (Turmeric rhizome)

Curcuminoids (curcumin 0.3-5.4 %).

The lipid-lowering effects of curcuminoids are due to alter-ations of cholesterol to bile aci-ds (Kamal-Eldin et al 2000; Ramirez-Tortosa et al 1999).

0.2 g curcuminoids per 100 g diet experience a reduction in TC and TGs in rats (Asai et al 2001).

Zingiber officinale (Ginger rhizome)

Gingerols and shogaols. 1- They inhibit cholesterol bio-synthesis (Tanabe et al 1993).

2- Ginger enhances the activity of hepatic cholesterol-7-hy-droxylase. It is the rate-lim-iting enzyme in bile acids biosynthesis, which stim-ulates cholesterol converse-on to bile acids, an impor-tant mechanism for elimina-ting cholesterol from the body (Srinivasan et al 1991)

1- Oral administeration of EtOH extract (22 mg/kg) reduced lipid after 10 we-eks in rats fed a choleste-rol rich diet.

2- This dose of ginger was found to produce similar results as gemfrimbrozil (Bhandari et al 1998).

Silybum marianum (Milk thistle seeds)

60 % silymarin. Silymarin inhibits cholesterol absorption. Silymarin caused an increase in HDL-C which is beneficial to treatment of atherosclerosis (Radjabian et al, 2010).

Silymarin consists of four flavonolignans of silybin-in (~50 to 60 %), isosyl-ibinin (~5 %), silychristin (~20 %) and silydanin (~10 %). The main active compound is believed to be silybinin.

Cinnamomum tamala (Leaves)

Flavonoids and polyphenols.

H2O and EtOH extracts imp-roved the serum lipid profile in rats by decreasing serum TC, TG, LDL-C, and increasing serum HDL-C, thus improving the atherogenic index.

1- Dose 400 mg/kg EtOH or H2O extracts of leaves (Dhulasavant et al 2011).

2- The leaves extract has preventive and curative effect against hyperlipidemia.

Hibiscus sabdariffa (Roselle flower and leaves)

Anthocyanins, flavonols, and protocatechuic acid.

1- It increases inhibition of intestinal absorption of cho-lesterol and interfers with lipoprotein production.

2- It increases expression of hepatic LDLR and their protection leading to an increased removal of LDL-

EtOH extract showed signifi-cant antihyperlipidemic acti-vity comparable to lovas-tatin.



C from the blood. 3- It increases degradation and

catabolism of cholesterol from the body (Ochani et al 2009).

Trigonella foenum-graecum (Fenugreek seeds)

Mucilage, proteins, fats, fibers, and saponins (diosgenin and tigogenin).

1- Diosgenin and tigogenin affect cholesterol metabol-ism in the liver.

2- Its fibres inhibit cholesterol intestinal absorption by abs-orbing bile acids which are subsequently lost in the fec-es.

3- Amino acid pattern of fenu-greek proteins can signifi-cantly lower serum cholest-erol levels in experimental animals (Valette et al 1984).

Terminalia arjuna Tannins, triterpenoidal saponins, flavonoids, proanthocyanidins, and other polyphenols.

1- EtOH extract interfers with the absorption of dietary cholesterol as well as bile acids from the intestine.

2- It increases elimination of fecal sterols and stimulation of bile acid synthesis may lead to increase utilization of cellular free cholesterol (Subramanian et al 2011).

Jatropha tanjorensis Polyphenols, steroids, terpenoids, and saponins.

Saponins and polyphenols bind with bile salt and chole-sterol in the intestinal tract lead to reduction of blood cholesterol by preventing its reabsorption (Oyewole et al 2011).

Whole grains as wheat, oats, corn, barley, psylli-um, oat bran, chitosan, cellulose, pectin, guar gum, and lignin

Dietary fibers Beta-glucan

1- They can decrease cholest-erol by absorbing dietary fats in the GI tract, preve-nting systemic absorption, and increasing cholesterol elimination in fecal bile acids (Anderson, et al 1994, 2000).

2-Beta-glucan increases the viscosity of food in the sto-mach and delays absorption (Brown et al 1998).

1- 10-12 g of blond psyllium per day can decrease TC by 3% to 14% and LDL-C by 5% to 10% (Davidson et al 1998).

2- Oat bran can reduce LDL-C by up to 26% in some patients (Brown et al 1999).

3- Chitosan might reduce serum lipids by adsorbing lipid molecules onto their surfaces (Chobot et al 1995).

Fish oil supplementation Omega-3 fatty acids (eic-osapentaenoic acid and docosahexaenoic acid )

Fish oil supplementation redu-ced TGs, but also raised LDL-C, especially those of high dose of fish oil (Farm-er et al 2001).

1- 1 g/dL of omega-3 fatty acids is needed to lower serum TG, which can be easily provided by adding fish to the diet. 2- 0.21 g EPS and 0.12 g DHA/day of omega-3 fatty acids have been shown to significantly lower serum TGs in hyperlipidemic patie-nts (Weber et al 2000).

Oenethera biennsis (Evening primrose oil)

Linoleic acid (LA) and gamma linolenic acid (GLA).

It lowers serum TC and LDL-C concentrations (Ishikawa et al 1989).

Evening primrose oil supple-ments (4 g daily) lowered serum cholesterol concentr-



ations by over 30%. Linum usitatissimum (Flaxseed/flaxseed oil)

α-Linolenic acid and omega-3 fatty acid.

The daily intake of flaxseeds leads to significant reduct-ion in TC and LDL-C. Flax-seed oil improves serum TG parameters (Finnegan et al 2003).

Olea europaea (Olive oil)

Oleic acid and phenolic compounds

1-Olive oil has a cholesterol-lowering effect.

2- Phenolic compounds offer protection against LDL oxi-dation and assist in the neu-tralization of free radicals to an extent at least equivalent to ascorbate and α-tocop-herol (Visioli et al 1995).

Sesamum indicum (Sesame oil)

Lignans (sesamin, sesaminol, and episesamin).

It reduces levels of serum TC. Sesaminol decreases lipid pero-xidase markers and increases the lag time before the lipid peroxidation propogation phase in vitro models (Kang et al 2000).

Table 13. Cholesteryl ester transfer protein inhibitors (CETP).



Turmeric and Laurel H2O extracts 1- The extracts inhibited the cellular uptake of oxidized LDL into macrophages, which is the initial step in atherogenesis.

2- They potently suppress the incidence of atherosclerosis via a strong antioxidant potential, prevention of apo A-I glycation, LDL phagocytosis, and inhibition of CETP (Jin et al 2011).

The extracts had potent CETP inhibitor ability (up to 23 % and 40 % inhibition, respectively) at a final concentration of 10 μg/mL.

Rubus fruticosus (Berries) Vitis vinifera (Grape) Red wine

Anthocyanins, flavans, quercetin, myricetin, kaempferol, and resveratrol or other phytochemicals.

1- Anthocyanins result in a dual beneficial effect in lowering LDL-C and raising HDL-C concentrations via the inhibition of CETP.

2- Lyophilized grape powder modestly lowered plasma LDL-C, apoB, and apoE in both pre- and postmenopausal women.

1- Anthocyanins may result in a greater reduction in CVD risk factors (Qin et al 2009).

2- Berry consumption increased serum HDL concentrations by 5.2%.

3- Red wine consumption for 4 weeks associated with a relative increase of 11-16% in HDL-C.

Table 14. AcylCoA:cholesterol acyltransferase inhibitors (ACAT).



Citrus fruits Flavonoid as naringenin. 1- Naringenin lowers the plasma and Naringenin supplementation



hepatic cholesterol concentrations by suppressing HMG-CoA reductase and ACAT (Lee et al 1999). 2- It inhibits apoB secretion primarily by inhibiting MTP and enhances LDLR-mediated containing lipoprotein uptake (Borradaile et al 2003).

caused a marked decrease in the excretion of fecal neutral sterols (242.9 mg/day) compared to the controls (521.9 mg/day).

Magnolia obovata leaves

Obovatol, honokiol, and magnolol.

They are new types of ACAT inhibitors.

They inhibit rat liver ACAT with IC50 values of 42, 71, and 86 µM, respectively (Kwon et al 1997).

Crataegus pinnatifida (Hawthorn fruit)

Triterpenic acids and pol-yphenols (eg, epicatechin, procyanidin B2, procyan-idin B5, procyanidin C1, hyperoside, isoquercitrin, and chlorogenic acid)

It reduces plasma cholesterol and TAG concentrations through the followings;

1- It reduces intestinal cholesterol absorption by inhibition of ACAT activity (in vitro).

2- It decreases plasma and liver cholesterol concentrations to a similar extent.

3- It increases fecal neutral sterol excretion.

4- It reduces fecal bile acid excretion (Rajendran et al 1996).

The fruit reduces cholesterol in rabbits fed a high cholesterol diet (Zhang et al 2002).

Campsis grandiflora (flower)

Triterpenoids Triterpenoids showed lower inhib-itory activity than oleic acid ani-lide (Kim et al 2005).

Rhus chinensis (Stem bark)

Tannin, flavonoid, coum-arin, hydroxy dammare-none, and semialactone

It inhibits ACAT. The plant used for the prevention and treatment of hypercholesterolemia, atherosclerosis, and dementia (Kim et al 2010).

Bauhinia purpurea (Butterfly tree, geranium tree)

Flavonoids, tannins, and proanthocyanidines

1- It reduces oxidation of LDL-C. 2- It inhibits dietary cholesterol

absorption and/or esterification by inhibition of pancreatic cholesterol esterase and intestinal ACAT.

3- It may direct inhibit cholesterol absorption or increases biliary excretion of sterol and/or bile acids.

4- It blocks cholesterol movement from the liver to the blood (Kwon et al 2011).

The EtOH extract of leaves has significant weight reduc-tion property compared to atorvastatin.

Table 15. Lanosterol synthase inhibitors.

Source Used part and/or active constituents Mechanism of action Comments

Colocasia esculenta

Mono and digalactosyldiacylglycerols It inhibits lanosterol synthase.

The EtOH extract showed 28-67% inhibition at concentration 300 µg/mL (Sakano et al 2005).

Table 16. AMP-activated protein kinase activators (AMPK).



Gynostemma pentaphyllum

Saponins (damulins A and B)

They activate AMPK (Nguyen et al 2011).

The activation of AMPK may contribute to beneficial effect of G. pentaphyllum on glucose and lipid metabolism.

Berberine It inhibited adipocyte differentiation PPAR is an important transcriptional



probably by inhibiting PPAR activity. regulator of adipogenesis. The activity of PPAR can be regulated by a variety of mechanisms including phosphorylation by members of the MAPK family (Lee et al 2006).

Resveratrol Resveratrol activated AMPK by incr-easing cytosolic calcium levels in a dose-dependent manner and at conce-ntration 40M and by promoting CaM-KKβ-dependent phosphorylation of AMPK (Vingtdeux et al 2010).

Myristica fragrans (Nutmeg fruit)

It activates the AMPK enzyme. 1- 5 µM of nutmeg extract produced strong AMPK stimulation.

2- Nutmeg and its active constituents can be used in metabolic disorders, hyperlipidemia, obesity, and type-2 diabetes (Nguyen et al 2010).

Peroxisome proliferator activated receptor (PPAR) activators

PPARs are ligand-activated transcription factors belonging to the nuclear receptor

superfamily. They include steroid and thyroid hormone receptors. These are activators of key metabolic pathways that control fatty acid oxidation, adipocyte differentiation, and insulin sensitivity (Le et al 2003). PPAR-α is expressed in liver, heart, muscle, and kidney. It regulates fatty acid catabolism. PPAR- is highly enriched in adipocytes and macrophages and involved in adipocyte differentiation, lipid storage, and glucose homeostasis (Gurnell et al 2003). PPAR-β is expressed ubiquitously with a less well defined function. The following table 17 contains some natural PPAR activators. Table 17. PPAR Activators.

Source Activated PPAR Active constitutes and comments

Pseudolarix kaempferi (root and trunk barks)

1-PPAR-α 2-Weak activator of

PPAR-β and γ

Pseudolaric acid B (Jaradat et al 2003).

Cannabis sativa PPAR-γ Ajulemic acid (synthetic analogue of the tetrahydrocannabinol (THC) metabolite (THC-11-oic acid) (Liu et al 2003).

Flavonoids PPAR-γ Apigenin-5µM (EC50) Chrysin-10µM (EC50) Kaempferol-10µM (EC50) (Liang et al 2001).

Grape fruit PPAR-γ Naringenin (Harmon et al 2000). Poria cocos Wolf PPAR-γ Dehydrotrametenolic acid (Sato et al 2002). Glycyrrhiza uralensis Fisher

PPAR-γ Prenyl flavonoids (Glycycoumarin, glycyrin, dehydroglyasperin C and dehydroglyasperin D) (Kuroda et al 2003; Mae et al 2003).

Saururus chinensis roots

PPAR-γ Saurufuran A-16.7µM (EC50) (Hwang et al 2002).

Soy Phytoestrogen PPAR-γ Genistein, (Dang et al 2003). Panax radix palva PPAR-γ Ginsenosides (Chung et al 2001). SUPRO-Soy brand PPAR-α and PPAR-

γ High-Soy isoflavone protein (Mezei et al 2003).

Momordica charantia (Bitter Gourd)

PPAR-α and PPAR-γ

Cucurbitane triterpenoids (Charantin) (Chao et al 2003).

Terpenoids (Isoprenols)

PPAR-α and PPAR-γ

Farnesol- 5.5µM and 28µM (EC 50 for PPAR-α and PPAR-γ activation, respectively) Geranylgeraniol-62µM and 60µM (EC50 for PPAR-α and PPAR-γ activation, respectively) (Takahashi et al 2002).



Table 18. Diacylglycerol acyltransferase inhibitors (DGAT).

Source Used part and/or active constituents component


Xanthohumol (XN)

XN is a plant chalcone. 1- It inhibits apoB secretion. This decrease was associated with increased cellular apoB degradation. 2- XN decreases MTP activity, which inhibits the synthesis of TG in the microsomal membrane and the transfer of this newly synthesized TG to the microsomal lumen. 3- It inhibits of TG synthesis by a reduction in DGAT activity, which leads to a decrease in DGAT-1 mRNA expression.

1-XN decreased MTP activity in a dose-dependent manner (as much as 30%). 2- The reduction in TG accumulation in the microsomal lumen is predominantly due to DGAT and/or MTP activity remains unknown. XN is a potent inhibitor of secretion (Casaschi et al 2004).

Table 19. Squalene synthase inhibitors.

Source Used part and/or

active constituents Mechanism of action Comments

Coelomycetes (Phoma species)

Squalestatin 1

Squalestatin 1 is a potent and selective inhibitor of squalene synthase, a key enzyme in cholesterol biosynthesis.

1- In vitro, 50 % inhibition of enzyme activity is observed at a concentration of 12-25 nM (range of 4-22 nM).

2- Squalestatin 1 lowers serum cholesterol by up to 75 % (Baxter et al 1992).

Plant thyroid hormone analogs

There were fewer studies about thyroid hormone (T3 and T4) analogs in plants.

Rhodiola rosea was used as a viable alternative treatment for the symptoms of short-term hypothyroidism in patients who require hormone withdrawal (Zubeldia et al 2010). Genistein and daidzein are the flavonoid components of soy. They influence thyroid hormone synthesis by inhibition of the iodide oxidizing enzyme thyroperoxidase. F21388 is a synthetic flav-onoid, which is structurally similar to thyroxine. It crosses the placenta and also reaches the fetal brain of animal models (Hamann et al 2008). The cruciferous family was also referred as thyroid modulators in plant (Horn-Ross et al 2002). Table 20. Miscellaneous.



Soy bean Soy protein and isoflavones

Soy protein significantly lowers TC, LDL-C, and TG. No change in HDL-C was noted (Anderson et al 1995).

Recent studies have shown that 20-50 g/d soy protein reduce LDL-C in patients with mild elevation of cholesterol who are following a low saturated fat diet (Teixeira et al 2000; Crouse et al 1999).

Commiphora mukul (Guggul)

Guggulsterones (4,17(20)-pregnadiene-3,16 dione).

Guggulsterones prevent oxidation of LDL (Urizar et al 2002) and antagonize the farnesoil X receptor

1- The FXR receptor controls cholesterol by regulating the level of bile acids in the body. Blocking the action of FXR helps the body rid itself of more cholesterol.



(FXR), a nuclear hormone receptor that is activated by bile acids.

(Nityanand et al 1971). 2- Guggul is to be effective as clofibrate in

reducing cholesterol level (Singh et al 1994).

3- Guggul decreased TC level by 11.7 %, LDL-C by 12.5 %, TG by 12.0 %, with no change noted in HDL-C.

Wine (alcohol) Polyphenolic compounds (as resveratrol) (Rotondo et al 2001)

It reduces insulin resist-ance, lower blood pressure and increase HDL-C (Eag-les et al 1998).

1- One or two drinks per day. 2- The polypheolic compounds have been shown

to prevent lipoprotein oxidation in vitro.

Weight loss Weight loss in most obese individuals tends to incre-ase plasma HDL-C levels, as well as decreasing TG levels (Carmena et al 2001).

1- Obesity is often associated with elevated TG and low level of HDL-C (Grundy et al 1990).

2- Elevation of TGs lead to increased catabolism of TG rich HDL-C, resulting in lower levels of HDL-C (Rashid et al 2002).

3- One should replace saturated fat with mon-ounsaturated fats in any weight loss prog-ram designed to increase HDL-C (Gordon 1998).

Flavonoids rich herbs (fru-its, vegetables, and beverages)

Flavonoids Polyphenolic flavonoids are reducing plasma chol-esterol levels and/or thro-ugh the inhibition of LDL oxidation (Xia et al 1998; Fuhrman et al 1997).

Licorice extract (free of glycyrrhizic acid) and isoflavone glabridin have shown marked inhibition of LDL oxidation in 10 normo-lipidemic individuals (Yang et al 2001).

Dietary Recommendations Dietary intervention is the primary treatment strategy. Diet is regarded to be the cornerstone of hyperlipidaemia management and has been shown to produce reductions in cholesterol levels and in cardiovascular and overall mortality. The main component of antihyperl-ipidemia diet is a food pattern that is low in saturated fat and dietary cholesterol and provides adequate energy to support growth and maintain an appropriate weight. Specific dietary recommendations include: Decreased intakes of saturated fat as stick margarine, partially hydrogenated oils and

fats, hydrogenated peanut butters, commercial bakery products, commercial fried food (e.g., French fries), and high fat animal products.

Decreased intakes of dietary cholesterol. Encourage a low to moderate total fat intake. Balance the fatty acid composition of diet by polyunsaturated and monounsaturated

fatty acids, which can lower LDL. Encourage consumption of omega-3-fatty acids due to their association with lower

TG and other cardioprotective effects. Increase dietary fiber intake because soluble fiber can contribute to LDL reduction.

Fruits, vegetables, cereals, oats, whole grains, and legumes are good sources of solu-ble fiber.

Encourage antioxidant-rich food as whole grains, citrus fruits, melons, berries and dark orange/yellow or leafy green vegetables rather than supplements.

Conclusion

Hyperlipidaemia is established as a major health concern due to strong causal relat-

ionships with ischaemic heart disease, ischaemic stroke, overall mortality, and its high prev-



alence. There is also strong evidence of the efficacy of cholesterol-lowering in reducing morbidity and mortality related to hyperlipidaemia. Several classes of drugs are used to treat hyperlipidemia. These classes differ not only in their mechanism of action but also in the type and magnitude of lipid reduction. Historically, natural products have provided an endless source of medicine. As a unique system in complementary and alternative medicine, medicinal plants hold great potential in the control of lipid metabolism and provide new effective therapies. The hypolipidemic activities of many herbal medicines have been proved in well-designed animal experiments. Mixtures of interacting compounds as omega-3-fatty acids, resveratrol, apigenin, genistein, quercetin, berberine, curcuminoids, and ginsenosides produced by plants may provide important combination therapies that simultaneously aff-ect multiple pharmacological targets and provide clinical efficacy beyond that of single compound-based drugs. The major advantage of natural hypolipidemic drugs over synthetic drugs is that many natural drugs exhibited their hypolipidemic activity by different mechan-isms as garlic, turmeric, citrus fruit, soya beans, Bauhinia purpurea, tea, plant sterols, beber-ine, and naringenin. Many of these herbal medicines are finding their way onto the world market as alternatives to prescribed drugs currently available to treat of hyperlipidemia. At the end, patients with hyperlipidemia should change their lifestyle like exercising and eating a healthy diet can also lower their lipid levels and are often the first step in treatment. List of abbreviations and definitions.

List of abbreviations and definitions

2-MAG 2-Monoacylglycerol IRS Insulin Receptor Substrate ABCA1 ATP-Binding Cassette Protein A1 LA linoleic acid ACAT Acyl Coenzyme A:Cholesterol Acyl

Transferase LCAT Lecithin-Cholesterol Acyl Transferase

AHA American Heart Association LDL Low Density Lipoprotein AMPK AMP kinase LDL-C Low Density Lipoprotein

Cholesterol ApoB Apolipoprotein B LDLR Low Density Lipoprotein receptor apoB100 Apolipoprotein B100 LDLR-D LDL receptor-deficient ApoC-III apolipoprotein C-III LPL Lipoprotein Lipase ApoE ApolipoproteinE LRP LDL Receptor-related Protein ASCVD Atherosclerotic cardiovascular disease MDA Malondialdehyde ASO Antisense oligonucleotides MTP Microsomal Triglyceride Transfer Protein ATP Adenosine Triphosphate mRNA Messenger Ribonucleic Acid CAD Coronary Artery Disease NARC-1 neural apoptosis-regulated convertase 1 CETP Cholesteryl Ester Transfer Protein NCEPEP National Cholesterol Education Program

Expert Panel CH Cholesterol 7α-hydroxylase Non-HDL Non High Density Lipoprotein Cholesterol CHD Coronary Heart Disease P 407 Poloxamer 407 CVD Cardiovascular Diseases PCSK 9 Proprotein Convertase Subtilisin/Kexin 9 DGAT Diacylglycerol acyltransferase inhibitors PI3K Phosphatidylinositol 3-kinase DHA Docosahexaenoic Acid PL Phospholipids EPS FATPs

Eicosapentaenoic Acid Fatty Acid Transport Proteins

PPARs Peroxisome Proliferator Activated Receptors

FCH Familial combined hyperlipoproteinemia pPLA2 Pancreatic Phospholipase A2 FDA Food Drug Administration siRNA Small interfering RNAs FDBL Familial Dysbetalipoproteinemia SR-B1 Scavenger Receptor Class B1 FFA Free Fatty Acids SREBPs Sterol regulatory element-binding

proteins FPP Farnesyl Pyrophosphate STZ Streptozotocin FXR Farnesoil X Receptor TAG Triacylglycerol GLA Gamma Linolenic Acid TC Total Cholesterol



HCD High Cholesterol Diet TG Triglyceride HDL High Density Lipoproteins TRE Thyroid Hormone Responsive Element HDL-C High Density Lipoprotein Cholesterol VLDL Very Low Density Lipoprotein HFD High Fat Diet WHO World Health Organization HL Hepatic Lipase XN Xanthohumol HMG-CoA 3-Hydroxy-3-Methylglutaryl Coenzyme

A ZA Zaragozic Acid

IDL Intermediate Density Lipoproteins

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Natural antihyperlipidemic agents: Current status and future perspectives

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