Cholesterol metabolism

Cholesterol Cholesterol is the precursor of all other steroids Plays an important structural role in membranes Cholesterol is synthesized from acetyl-CoA Cholesterol synthesis in the liver is regulated Excess cholesterol is excreted from the liver

Reverse cholesterol transport Plasma low-density lipoprotein (LDL) is the vehicle of uptake of cholesterol and cholesteryl ester into many tissues Reverse cholesterol transport Free cholesterol is removed from tissues by plasma high-density lipoprotein (HDL) and transported to the liver Eliminated from the body either unchanged or after conversion to bile acids

CHOLESTEROL is derived about equally FROM THE DIET & FROM BIOSYNTHESIS Endoplasmic reticulum and the cytosol. The biosynthesis of cholesterol may be divided into five steps Synthesis of mevalonate Formation of Isoprenoid units

Six isoprenoid units condense to form squalene Squalene cyclizes to give rise to lanosterol. Cholesterol is formed from lanosterol

Regulation of cholesterol synthesis at the HMG-CoA reductase step In starving animals is accompanied by a decrease in the activity Inhibited by dietary cholesterol Hepatic synthesis Regulating the rate of protein synthesis Posttranslational modification Increase HMG-CoA reductase activity Insulin or thyroid hormone Decrease Glucagon or glucocorticoids

Regulation of cholesterol synthesis In the liver regulated partly by cholesterol in the diet In tissues Cholesterol balance is maintained between the factors causing gain of cholesterol and the factors causing loss of cholesterol

FACTORS INFLUENCE THE CHOLESTEROL BALANCE IN TISSUES Cell cholesterol increase is due to Uptake of cholesterol-containing lipoproteins By receptors, eg, The LDL receptor The scavenger receptor Uptake of free cholesterol from cholesterol-rich lipoproteins to the cell membrane Cholesterol synthesis Hydrolysis of cholesteryl esters by the enzyme cholesteryl ester hydrolase

FACTORS INFLUENCE THE CHOLESTEROL BALANCE IN TISSUES Decrease is due to efflux of cholesterol from the membrane to HDL esterification of cholesterol Utilization of cholesterol for synthesis of other steroids

The LDL Receptor High-affinity Low-affinity Scavenger pathway The apo B-100, E receptor Highly Regulated Low-affinity not regulated Scavenger pathway

Influx of cholesterol Inhibits HMG-CoA synthase, HMG-CoA reductase Stimulates ACAT activity Down-regulates synthesis of the LDL receptor

Transport of cholesterol between the tissues in humans.

Reverse cholesterol transport HDL (preβ-HDL, discoidal, or HDL3) takes up cholesterol from the tissues and LCAT esterifies it and deposits it in the core of HDL, which is converted to HDL2. The cholesteryl ester in HDL2 is taken up by the liver, either directly or after transfer to VLDL, IDL, or LDL via the cholesteryl ester transfer protein.

CHOLESTEROL IS EXCRETED FROM THE BODY AS CHOLESTEROL BILE ACIDS (SALTS) a major pathway for the elimination of cholesterol.

Atherosclerosis & Coronary Heart Disease HDL (HDL2) concentrations and coronary heart disease the most predictive relationship is the LDL:HDL cholesterol ratio.

Diet Can Play an Important Role in Reducing Serum Cholesterol polyunsaturated and monounsaturated fatty acids Up-regulation of LDL receptors Saturated fatty acids cause the formation of smaller VLDL particles Contain relatively more cholesterol Utilized by extrahepatic tissues at a slower rate

Factors associated with elevation of plasma FFA Regular exercise Lowers plasma LDL Raises HDL

Reduction of Serum Cholesterol & Triacylglycerol Diet Hypolipidemic Drugs Block the reabsorption of bile acids cholestyramine resin blocking the absorption of cholesterol Sitosterol Statins Clofibrate and gemfibrozil decreasing the secretion of triacylglycerol and cholesterol-containing VLDL by the liver Stimulate hydrolysis of VLDL

Reduction of Serum Cholesterol & Triacylglycerol Probucol increase LDL catabolism via receptor independent Pathways Antioxidant properties Nicotinic acid inhibiting adipose tissue lipolysis reduces the flux of FFA Inhibiting VLDL production by the liver.

Disorders of the Plasma Lipoproteins Primary (Dyslipoproteinemias) Are Inherited Secondary abnormal lipoprotein patterns