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CHOLESTEROL SYNTHESIS

,
TRANSPORT, AND EXCRETION

AT THE END OF THIS LECTURE
YOU ARE EXPECTED TO:
• Give the biological importance of
cholesterol
• Identify the characteristics of cholesterol
structure
• Name the essential steps towards the
synthesis of cholesterol
• Discuss how cholesterol synthesis is
regulated

AT THE END OF THIS LECTURE
YOU ARE EXPECTED TO:
• Identify factors that influence cholesterol
balance in the body
• Discuss how cholesterol is transported to
different body tissues
• Discuss how cholesterol is excreted from
the body
• Define some clinical conditions related to
abnormal cholesterol metabolism

BIOLOGIC IMPORTANCE OF
CHOLESTEROL
• Structural component
of all cell membranes
• Modulates membrane
fluidity
• At temperatures
below melting
temperature, it
increases membrane
fluidity

cholesterol causes atherosclerotic plaque formation and leads to an increased risk for coronary artery disease . and Vitamin D • Cholesterol is a component of plasma lipoproteins sent to the peripheral tissues • When produced in excess.BIOLOGIC IMPORTANCE OF CHOLESTEROL • Cholesterol is a precursor of bile acids. steroid hormones.

CHOLESTEROL STRUCTURE • Highly hydrophobic • Has 4 fused hydrophobic rings (steroid nucleus) with 8-carbon branched hydrocarbon chain attached to C-17 of the D ring • Ring A has a hydroxyl group at C3 • Ring B has a double bond between C5 and C6 • Steroids with 8 to 10 carbon atoms in the side chain at C17 and a hydroxyl group at C3 are called sterols • Cholesterol is the major sterol in animal tissues .

CHOLESTERYL ESTERS (CE) • Most plasma cholesterol is in an esterified form with a fatty acid attached at C3 • This makes the structure even more hydrophobic than free cholesterol • Not normally found in membranes • Must be transported in association with a protein (lipoprotein). or be solubilized by phospholipids and bile salts in bile .

SYNTHESIS OF CHOLESTEROL .

and reproductive tissues • All C atoms are from acetate • NADPH provides reducing equivalents • Synthesis occurs in the cytoplasm.OVERVIEW • Cholesterol is synthesized by virtually all tissues. with enzymes in both cytosol and ER membrane . adrenal cortex. but is largely contributed by the liver. intestine.

SYNTHESIS OF 3-HYDROXY-3METHYGLUTARYL CoA (HMG CoA) • Similar to the pathway that produces ketone bodies • In the liver. while the mitochondrial enzyme synthesizes ketone bodies . the cytosolic HMG CoA synthase participates in cholesterol synthesis.

Atorvasatin.SYNTHESIS OF MEVALONIC ACID (MEVALONATE) • Rate-limiting step in cholesterol synthesis • Irreversible • Occurs in the cytosol • HMG CoA reductase is an intrinsic membrane protein of the ER with the catalytic domain projecting into the cytosol • This step is inhibited by statins (Simvastatin.) HO H2C C  O C CH2 O C SCoA HMG-CoA HMG-CoA Reductase 2NADP+ + HSCoA HO  C O O 2NADPH H2C CH3 C CH3 CH2 O H2 C OH mevalonate . etc.

Mevalonate (6C) is converted to Mevalonate 5 phosphate in 2 steps requiring ATP 2. IPP (5C) is synthesized by decarboxylation. A second molecule of IPP condenses with GPP to form a 15-C FPP . It is the precursor of the isoprenoids 3.CHOLESTEROL SYNTHESIS 1. IPP is isomerized to DPP 4. IPP and DPP condense to form the 10-carbon GPP 5.

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and are reduced to form Squalene (30C) 7.CHOLESTEROL SYNTHESIS 6. Migration of double bond form C8 to C5 d. This involves: a. Two molecules of FPP combine. Squalene is converted to lanosterol in a series of steps. Removal of 2 methyl groups at C4 c. Squalene hydroxylation triggers cyclization to lanosterol 8. releasing pyrophosphate. Shortening of C chain from 30 to 27 b. A multistep process converts lanosterol to cholesterol. Reduction of the double bond between C24 and C25 .

• Many of the reactions involved in converting lanosterol to cholesterol and other steroids are catalyzed by members of the cytochrome P450 enzyme superfamily .

an intermediate on the pathway for cholesterol synthesis.Farnesyl pyrophosphate. also serves also as precursor for synthesis of various non-steroidal isoprenoids. .

FARNESYL PYROPHOSPHATE/DIPHOSPHATE GIVES RISE TO: DOLICHOL for the synthesis of N-glycosides UBIQUINONE or coenzyme Q for the Electron Transport Chain .

cholesterol. and statin drugs • It is only hepatic synthesis that is inhibited by dietary cholesterol • Insulin or thyroid hormone increases HMG CoA reductase activity. which is inhibited by mevalonate. while glucagon or glucocorticoids decrease it .REGULATION OF CHOLESTEROL SYNTHESIS • Major control point is the reaction catalyzed by HMG CoA reductase.

FACTORS THAT INFLUENCE CHOLESTEROL BALANCE IN TISSUES .

CELL CHOLESTEROL INCREASE IS DUE TO: • Uptake of cholesterol-containing lipoproteins by receptors • Uptake of free cholesterol from cholesterol-rich lipoproteins to the cell membrane • Cholesterol synthesis • Hydrolysis of cholesteryl esters by the enzyme cholesteryl ester hydrolase .

or bile acids in the liver . LCAT is also known as PCAT • Esterification of cholesterol by ACAT (AcylCoA:cholesterol acyltransferase) • Utilization of cholesterol for synthesis of other steroids.CELL CHOLESTEROL DECREASE IS DUE TO: • Efflux of cholesterol from the cell membrane to HDL promoted by LCAT (lecithin:cholesterol acyltransferase). such as hormones.

and LDL in exchange for TAG. IDL. facilitating reverse cholesterol transport .ROLE OF CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) IN PLASMA LIPID TRANSPORT • CETP facilitates the transfer of CE from HDL to VLDL. • This allows LCAT conversion of free cholesterol to CE.

When TAG synthesis exceeds VLDL synthesis.METABOLISM OF LDL AND THE ROLE OF THE LDL RECEPTOR • VLDL is produced from the liver and is composed mostly of TAG • VLDL transfers TAG from liver to tissues. it results in fatty liver • VLDL is the precursor of LDL • LDL contains less TAG than VLDL • LDL has a high concentration of cholesterol and cholesteryl esters .

or return cholesterol to the liver • LDL binds to cell surface receptors that recognize apolipoprotein B-100 .METABOLISM OF LDL AND THE ROLE OF THE LDL RECEPTOR • The primary function of LDL is to provide cholesterol to the peripheral tissues.

DEGRADATION OF CHOLESTEROL .

• The ring structure of cholesterol cannot be metabolized to carbon dioxide and water in humans • The intact sterol nucleus is eliminated by conversion to bile acids and bile salts • Bile acids and bile salts are excreted in the feces • Some cholesterol is also secreted into the bile .

the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol. .• Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol • However.

• Some of the cholesterol in the intestine is modified by bacteria before excretion • The primary compound made is coprostanol. a reduced derivative of cholesterol .

or be stored in the gallbladder .BILE • Consists of a watery mixture of organic and inorganic compounds • Lecithin and bile salts (conjugated bile acids) are quantitatively the most important organic components of bile • Can pass directly from the liver where it is synthesized to the duodenum through the common bile duct.

STRUCTURE OF BILE ACIDS • Contains 24 carbons with 2 or 3 hydroxyl groups and a side chain that terminates in a carboxyl group • Has a pKa of 6 and is not fully ionized at physiologic pH • Amphipathic. with the hydroxyl groups above the plane of the steroid ring and the methyl groups below the plane • Act as emulsifying agents to prepare fats for degradation PRIMARY BILE ACIDS .

• The reaction catalyzed by the 7α-hydroxylase is the rate limiting step in bile acid synthesis • This step is down-regulated by cholic acid and upregulated by cholesterol .

SYNTHESIS OF BILE SALTS • Before the bile acids leave the liver. they are conjugated to a molecule of either glycine or taurine by an amide bond between the carboxyl group of the bile acid and the amino group of the added compound • Conjugation takes place in peroxisomes .

bile salts are more effective solubilizers .• The ratio of glycine to taurine forms in the bile is 3:1 • The salt forms are fully ionized (negatively charged) at physiologic pH • Because of their enhanced amphipathic nature.

ACTION OF INTESTINAL FLORA ON BILE SALTS • Bacteria in the intestine can remove glycine and taurine and regenerate bile acids • They can also form secondary bile acids through deconjugation and dehydroxylation OH DEOXYCHOLIC ACID FROM GLYCOCHOLIC ACID OH LITHOCHOLIC ACID FROM CHENODEOXYCHOLIC ACID .

and are reused • Only 0. pass through the portal vein. they are carried by albumin noncovalently through the circulation . more than 95% are reabsorbed through the ileum.5 g are lost in the feces • Because bile acids are hydrophobic.ENTEROHEPATIC CIRCULATION OF BILE ACIDS AND BILE SALTS • Of the 15 to 30 grams of bile salts secreted from the liver.

• Bile acid sequestrants like cholestyramine bind bile acids in the gut and prevent their reabsorption. promoting cholesterol excretion • Dietary fiber also binds bile acids and promotes their excretion .

CLINICAL ASPECTS .

This is one of the benefits provided by exercise .ATHEROSCLEROSIS AND CORONARY HEART DISEASE • Atherosclerosis is due to the deposition of cholesterol and cholesteryl ester from the plasma lipoproteins to the artery walls • A high HDL and low LDL protects a person from this complication.

or destruction • Not all are harmful • Diseases such as Diabetes Mellitus. and atherosclerosis exhibit abnormal lipoprotein patterns that resemble dyslipoproteinemias . Kidney disease. transport. Hypothyroidism.DYSLIPOPROTEINEMIAS • Due to various defects in lipoprotein formation.

but administration of chenodeoxycholic acid may help to supplement the body’s supply of bile acids .CHOLELITHIASIS (GALLSTONES) • Occurs when more cholesterol enters the bile than can be solubilized by the bile salts and lecithin present • Surgery is the treatment of choice.