Cholesterol metabolism Cholesterol Cholesterol is the precursor of
Cholesterol metabolism
Cholesterol • Cholesterol is the precursor of all other steroids • Plays an important structural role in membranes • Cholesterol is synthesized from acetyl-Co. A • Cholesterol synthesis in the liver is regulated • Excess cholesterol is excreted from the liver
• 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-Co. A 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-Co. A 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 – The apo B-100, E receptor – Highly Regulated • Low-affinity – not regulated • Scavenger pathway
• Influx of cholesterol – Inhibits HMG-Co. A synthase, HMG-Co. A 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 HDL 3) takes up cholesterol from the tissues and LCAT esterifies it and deposits it in the core of HDL, which is converted to HDL 2. • The cholesteryl ester in HDL 2 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 (HDL 2) 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 cholesterolcontaining 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
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