Cholesterol synthesis and breakdown Dr. Carolyn K. Suzuki 1.

Cholesterol synthesis and breakdown

Dr. Carolyn K. Suzuki

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To compare and contrast the different mechanisms by which cholesterol biosynthesis are regulated.

To predict whether intracellular cholesterol synthesis will be up- or down-regulated in response to energy availability as influenced by diet, hormones and exercise.

To distinguish the different mechanisms by which plasma cholesterol levels are controlled by clinically adminstrered pharmacological agents.

OBJECTIVES

Cholesterol in cellular membranes

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hydrocarbon tail

steroid nucleusA

C D

B

cholesterolCholesterol•27 carbons all derived from acetate•C-3 hydroxyl group•C-17 side chain with 8 carbons

Sources in the body• synthesized primarily in liver and intestine• not required in diet• intestinal uptake from diet

Elimination• converted into bile acids and bile salts in liver• stored in gall bladder, secreted into intestine• small % excreted in feces

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3

cholesterol ester

fatty acid

A

C D

B

Cholesterol esters• esterification at C-3 with fatty acid• primary form transported in plasma• packaged in lipoprotein particles

(e.g. LDL, HDL)

cytosolmitochondriaperoxisomes

A. Synthesis of HMG CoA

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2 acetyl CoA (2C)

2 acetoacetyl CoA (4C)

3-hydroxy-3-methylglutaryl CoA (6C)(HMG CoA)

thiolase

HMG CoA synthase

CoA

CoA

acetyl CoA

endoplasmicreticulum

B. Synthesis of mevalonic acid

HMG CoA (6C)

HMG CoA reductase2 NADPH

2 NADP+CoA

Mevalonic acid (6C)

RATE LIMITING STEP

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C. Cholesterol synthesis

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C. Cholesterol synthesis

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The transcription factor regulating cholesterol synthesis genes is SREBP- sterol responsive element binding protein

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SCAP- SREBP Cleavage Activating Protein a transmembrane protein has a sterol sensing domain binds to SREBP in the ER when ER sterols are low, SCAP-SREBP move to the GolgiProtease 1 and Protease 2- localized to the Golgi responsible for the two step cleavage of SREBP resulting in soluble, cytosolic SREBP

Mature, proteolytically-processed SREBP translocates from the Golgi to the nucleus activates the expression of cholesterol synthesis genes

SREBP- Sterol Regulatory Element Binding Protein a transmembrane protein has a DNA binding domain has a SCAP interacting domain

Sterol-dependent regulation of cholesterol synthesis genes

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nucleus

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SCAP and SREBPare transported to

the Golgi

when sterol levelsare low

step #1

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step #2

step #3

SREBP release

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SREBPtranslocatesto nucleus

step #4

transcriptional activation of sterol responsive element (SRE)

controlled genes

nucleus

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When intracellular cholesterol is low

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Cholesterol-dependent degradation of HMG CoA reductase

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(AMP kinase)

AMP kinase is different from cAMP-dependent kinase (PKA)

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Statins competitively inhibit HMGR-they mimic the transient intermediate mevadyl CoA

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Vytorin (ezetimibe + simvastatin)• ezetimibe administered in combination with a

simavastatin (i.e. a statin)• further reduces total cholesterol levels as compared

to statin alone• blocks cholesterol absorption in the intestine and

cholesterol synthesis in the liver• permits reduced doses of statins, which have

side effects

Zetia (ezetimibe)

Mechanism of action- • acts at small intestine brush border• does not enter the bloodstream, no side effects• inhibits absorption of cholesterol• does not block absorption of triglycerides or

fat-soluble vitamins

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Reduction of LDL-cholesterol across all tested statins

Mean %change in LDL-C

from baseline

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• cholesterol is the precursor of bile acids and bile salts• synthesized in the liver• stored in the gall bladder• secreted into intestine • aids digestion by emulsifying dietary lipids making them

accessible to pancreatic lipases• aids intestinal absorption of fat-soluble vitamins (A, D, E, K) • ~95% are reabsorbed in ileum and returned to liver• ~5% of bile salts are excreted in feces

Bile acids and bile salts

Excretion of bile salts is the principal mechanismfor eliminating cholesterol from the body

Enterohepatic circuit•synthesis in the liver•storage in the gall bladder•secretion into intestine•re-circulation to liver

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cholic acid-+ cholesterol

rate limiting step

Primary bile acidsare formed from

cholesterolcholesterol

cholic acid chenodeoxycholic acid

7--hydroxylase hydroxylation of C7addition of OH group

7--hydroxycholesterol

Primary bile acids

7--hydroxylase

cholic acid-

+ cholesterol

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• Hypercholesterolemia is often treated with “sequestrants” that bind bile acids in the intestine. These compounds:

prevent reabsorbtion of bile acidsincrease conversion of cholesterol to bile

acidsincrease bile salt elimination in feces

• Dietary fiber also sequesters bile acids

Secondary bile acids

Secondary bile acids

Primary bile acids

7--hydroxylase

cholic acid-+ cholesterol

30Increased elimination of cholesterol from the body

Secondary bile acids

Primary bile acids

Bile salts-glycine or taurine

conjugated tobile acids in liver5% lost in feces Recent R & D efforts focusing on bile acid receptors

as drug targets for treating liver disease, liver cancer, metabolic disease.

Review- you tell me !!!!

•How many carbons are there in cholesterol?

•Which carbons are the business ends of the cholesterol molecule?

•When cholesterol levels are high, HMG CoA reductase is regulated by which of the following mechanisms?

•When cholesterol levels are high, HMG CoA reductase is regulated by which of the following mechanisms?

•What organ STORES bile acids and bile salts?