Lipids Metabolism

Lipids MetabolismLipids Metabolism

Fatty acidsFatty acids: are stored in adipose tissue, in the form of

Triacylglycerol (TAG) = Glycerol + 3 Fatty Acids

TAGTAG: provide concentrated storage of metabolic energy

Complete oxidation of fatty acids Complete oxidation of fatty acids to CO2 & H2O:to CO2 & H2O: 9 Kcal/gram of fat 9 Kcal/gram of fat

Stored FatsStored Fats

Fatty Acids OxidationFatty Acids Oxidation

Release of fatty acids from TAGRelease of fatty acids from TAGin adipose tissuein adipose tissue

• By hormone-sensitive lipase (HSL) hormone-sensitive lipase (HSL) ---- yields free fatty acids

• GlucagonGlucagon & EpinephrineEpinephrine phosph. HSL ACTIVEACTIVE (in fasting statefasting state, nono glucose) cAMP

• Insulin Insulin dephosph. HSL INACTIVEINACTIVE (fed statefed state, glucose is available)

Fate of free fatty acids Fate of free fatty acids (released from TAG in adipose tissue)(released from TAG in adipose tissue)

freefree Fatty acids Fatty acids (from adipose tissue TAG)(from adipose tissue TAG)

Blood (bound with albumin)

Cells of body

FA OxidationFA Oxidation (in mitochondria)

Ketone Bodies Acetyl CoA Acetyl CoA Citric Acid Cycle (in liver)FFAs are oxidized in all tissues of the body EXCEPT:FFAs are oxidized in all tissues of the body EXCEPT:RBCsRBCs (no mitochondria) brainbrain (BBB)

-oxidation of fatty acids-oxidation of fatty acids

• Fatty acids in cytosol are transported to mitochondria

• -oxidation of fatty acids occurs In the mitochondria

• Two carbon fragments are successively removed from carboxyl end of the fatty acid producing acetyl CoA, NADH & FADH2

Fatty Acid Fatty Acid (n carbons) Fatty acid Fatty acid (n -2 carbons) + Acetl CoA Acetl CoA + NADH + FADH2

Transport of Fatty acids to mitochondriaTransport of Fatty acids to mitochondria

1- Long-chain fatty acids 1- Long-chain fatty acids FAs longer than 12 carbonsFAs longer than 12 carbons

• Long-chain fatty acids are transported to the mitochondria by carinitine carinitine using carnitine shuttlecarnitine shuttle

• Enzymes of the carinitine shuttle:Enzymes of the carinitine shuttle: Carnitine Acyltransferase-I (CAT-I) Carnitine Acyltransferase-II (CAT-II)

Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

Carinitine Shuttle & EnzymesCarinitine Shuttle & Enzymes

• Sources of carinitine:Sources of carinitine: - DietDiet : particularly in meat products - Synthesized: Synthesized: From amino acids lysine & methionine in liver & kidney BUT not: in sk.ms & heart

• Inhibitor of carinitine shuttleInhibitor of carinitine shuttle - occurrence of fatty acid synthesis fatty acid synthesis in the cytosol in the cytosol (indicated by malonyl CoA) - increased acetyl CoA / CoA ratioacetyl CoA / CoA ratio

Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

• Carnitine deficienciesCarnitine deficiencies Lead to decreased ability of tissues to use long-chain FAs as sources of fuel as they

are not transported to the mitochondria Secondary causes:Secondary causes: - liver diseases: decreased synthesis of carnitine - Malnutrition or strictly vegetarians: diminshed carnitine in food - Increased demand for carnitine e.g. In fever, pregnancy, etc - Hemodialysis due to removal of carnitine from blood

Primary carinitine deficiencies:Primary carinitine deficiencies: caused by congenital deficiencies of : - one of enzymes of the carnitine shuttle (next slide) - one of the components of renal tubular reabsorption o f carnitine - one of the components of carnitine uptake of carnitine by cells

Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

• CPT-I deficiency:CPT-I deficiency: - Affects the liver - liver is unable to utilize long-chain fatty acids as a fuel - So, liver cannotcannot perform gluconeogenesis (synthesis of glucose during fasting) Hypoglycemia occurs , might lead to comacoma

• CPT-II deficiency:CPT-II deficiency: - Affects primarily the skeletal & cardiac muscles - Symptoms : Cardiomyopathy Muscle weakness

• Treatment of carinitine deficienciesTreatment of carinitine deficiencies - Avoiding prolonged fasting - Diet should be rich in carbohydrates , low in long-chain fatty acids & supplemented with medium chain fatty acids

Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

2- Short- & medium- chain fatty acids2- Short- & medium- chain fatty acids FAs shorter than 12 carbons FAs shorter than 12 carbons

Can cross the inner mitochondrial membrane without aid of carinitine

Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

Reactions of Reactions of -oxidation-oxidation

Medium Chain Fatty acyl acyl CoA Dehydrogenase Deficiency Medium Chain Fatty acyl acyl CoA Dehydrogenase Deficiency (MCAD)(MCAD)

• Autosomal recessive disorderAutosomal recessive disorder• One of the most common inborn errors of metabolism• The most common inborn error of fatty acid oxidation (1:40000

worldwide births)• Cause decrease of fatty acid oxidation • Severe hypoglycemia Severe hypoglycemia occurs (as tissues do not get use fatty acids as a

source of energy & must rely on glucose)• Infants are particularly affected by MCAD deficiency as they rely on milk

which contains primarily MCAD• Treatment: carbohydrate rich dietTreatment: carbohydrate rich diet

Energy Yield from Fatty Acid OxidationEnergy Yield from Fatty Acid Oxidation

Palmitatic acid as an example:

• Complete -oxidation of palmotyl CoA (16 carbons) produces : - 8 acetyl CoA ----- Kreb Cycle TCA cycle ------ 8 X 12 = 96 ATP - 7 NADH ----------- ETC ----------------------------- 7 X 3 = 21 ATP - 7 FADH2---------- ETC ----------------------------- 7 X 2 = 14 ATP• -------------• All yield ---------------------------------------------------------131 ATPs

• Activation of fatty acid requires 2 ATP

• Net energy gained: 129 ATPs from one molecule of palmitate

Oxidation of Branched-Chain Fatty AcidsOxidation of Branched-Chain Fatty Acids

• Branched-chain fatty acids as phytanic acid is catabolised by -oxidation by -hydroxylase

• Deficiency of a-hydroxylase deficiency results in accumulation of phytanic acid in blood & tissues with mainly neurologic symptoms (Refsum diseaseRefsum disease)

It is treated by diet restriction to reduce disease progression

Ketone Bodies MetabolismKetone Bodies Metabolism

Ketone BodiesKetone Bodies

• Liver mitochondria can convert acetyl CoA derived from the oxidation of fatty acids to ketone bodies which are:

1- Acetoacetate1- Acetoacetate 2- 3-hydroxybutyrate (or 2- 3-hydroxybutyrate (or -hydroxybutyrate)-hydroxybutyrate) 3- Acetone (nonmetabolized side product)3- Acetone (nonmetabolized side product)

• Acetoacetate & 3-hydroxybutyrate synthesized in the liver are transported via blood to peripheral tissues

• In peripheral tissues, they can be converted to acetyl CoA

• Acetyl CoA is oxidized by citric acid cycle to yield energy (ATPs)

Ketone bodies are important sources of energy for peripheralKetone bodies are important sources of energy for peripheraltissues:tissues:

1- They are soluble in aqueous solution, so do not need to be incorporated into lipoproteins or carried by albumin as do other lipids

2- They are synthesized in the liver when amount of acetyl CoA exceeds oxidative capacity of liver

3- They are important sources of energy during prolonged periods of fasting especially for the brain as: - Can pass BBB (while FAs cannot) - Glucose in blood available in fasting is not sufficient

Ketone Bodies Ketone Bodies cont.

Synthesis of ketone bodies in the liverSynthesis of ketone bodies in the liver(Ketogenesis)(Ketogenesis)

• During a fast, liver is flooded by fatty acids fatty acids mobilized from adipose tissue

• FAs are oxidised to acetyl CoA acetyl CoA in large amounts • Acetyl CoA does not find enough oxalacetate to be incorporated in TCA cycle

• So, excess acetyl CoA is shifted to ketone bodies ketone bodies formation

Reactions of ketone bodies synthesisReactions of ketone bodies synthesis

Use of Ketone bodies by peripheral tissuesUse of Ketone bodies by peripheral tissues(Ketolysis)(Ketolysis)

• Liver cannotcannot use ketone bodies as a fuel• Use of ketone bodies occurs in peripheral tissuesperipheral tissues

3-hydroxybutyrate (KB)3-hydroxybutyrate (KB)

Acetoacetate (KB) Acetoacetate (KB)

Acetoacetyl CoAAcetoacetyl CoA

2 acetyl CoA 2 acetyl CoA

Ketogenesis & KetolysisKetogenesis & Ketolysis

Excessive Production of Ketone BodiesExcessive Production of Ketone Bodiesin Diabetes Mellitusin Diabetes Mellitus

Ketonemia Ketonemia (increased KB in blood)(increased KB in blood)

occurs when occurs when rate of production of ketone bodies (KETOGENESIS) rate of production of ketone bodies (KETOGENESIS)

is greater than is greater than rate of their use (KETOLYSIS)rate of their use (KETOLYSIS)

Excessive Production of Ketone BodiesExcessive Production of Ketone Bodiesin Diabetes Mellitusin Diabetes Mellitus

in uncontrolled type 1 DM (Insulin-dependent DM)in uncontrolled type 1 DM (Insulin-dependent DM)

Increased lipolysis in adipose tissues with increased FFAs in blood

High oxidation of fatty acids in liver

Excessive amounts of acetyl CoA+

Depletion of NAD+ pool (required by citric acid cycle)

Acetyl CoA is shifted to ketone bodies synthesis in liver

DIABETIC KETOACIDOSIS, (DKA)DIABETIC KETOACIDOSIS, (DKA)(with Ketonemia & ketonuria)(with Ketonemia & ketonuria)

Excessive Production of Ketone BodiesExcessive Production of Ketone Bodiesin Diabetes Mellitusin Diabetes Mellitus

Manifestations of Diabetic KetoacidosisManifestations of Diabetic Ketoacidosis• ketonemiaketonemia: KB in blood more than 3 mg/dl, may reach 90 mg/dl• KetonuriaKetonuria: KB in urine may reach 5000 mg/24 hours• Fruity odour on the breath Fruity odour on the breath :due to increased acetone production• Acidosis & acidemiaAcidosis & acidemia• DehydrationDehydration : due to increased urine volume due to excess excretion of KB

& glucose

Excessive Production of Ketone BodiesExcessive Production of Ketone Bodiesin Diabetes Mellitusin Diabetes Mellitus