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Cholesterol Metabolism PowerPoint Presentation

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Description : Check out this medical presentation on Atherosclerosis, which is titled "Cholesterol Metabolism", to know about the biological significance of cholesterol and the processes that determine the cholesterol balance.

Tags : Atherosclerosis, Cholesterol Metabolism, lipid constituent, cell membranes, steroid hormones, bile acids, biosynthesis, vitamin D, posttranslational modification, membrane proteins, High plasma cholesterol

Published on : Jun 02, 2021 | Views : 3605 | Downloads : 23

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Slide 1-

Cholesterol Metabolism
Slide 2-

Biological significance of cholesterol Cholesterol is an essential lipid constituent of cell membranes Cholesterol is a precursor of steroid hormones and of bile acids Intermediates of cholesterol biosynthesis are required to make vitamin D and for posttranslational modification of membrane proteins High plasma cholesterol promotes atherosclerosis
Slide 3-

Processes that determine the cholesterol balance intestinal uptake of dietary cholesterol de novo cholesterol synthesis synthesis of steroid hormones from cholesterol synthesis of bile acids from cholesterol, and their biliary secretion biliary secretion of surplus cholesterol in unmodified form
Slide 4-

Overview of cholesterol synthesis
Slide 5-

Initial activation steps in cholesterol synthesis
Slide 6-

Formation of a C10 intermediate
Slide 7-

Formation of C15 and C30 intermediates
Slide 8-

Squalene cyclization yields the first sterol intermediate
Slide 9-

Demethylation, desaturation and saturation steps convert lanosterol to cholesterol
Slide 10-

UV-dependent synthesis of cholecalciferol
Slide 11-

Sterol metabolism occurs in the smooth endoplasmic reticulum
Slide 12-

Transcriptional regulation of cholesterol synthesis starts in the endoplasmic reticulum
Slide 13-

When cholesterol is low, SREBP is sorted to the Golgi apparatus
Slide 14-

Proteolytic cleavage in the Golgi releases SREBP
Slide 15-

Lipoprotein structure
Slide 16-

Classification of plasma lipoproteins
Slide 17-

Two membrane proteins control the uptake of sterols from the intestine
Slide 18-

Plant sterol structures
Slide 19-

Structures of ABC transporters in the inward-open and outward-open conformations
Slide 20-

ABC transporters induce substrate “flip-flop” across the membrane
Slide 21-

Transport of cholesterol between the liver and peripheral tissues
Slide 22-

Stages of cholesterol transport Dietary cholesterol Packaged into chylomicrons, which turn into chylomicron remnants through triacylglycerol extraction by lipoprotein lipase Chylomicron remnants are taken up by the liver Liver cholesterol (from diet, or endogenously synthesized) Packaged into VLDL Lipoprotein lipase turns VLDL into IDL and then LDL LDL is taken up through receptor-mediated endocytosis in peripheral tissues
Slide 23-

Cholesterol transport (ctd.) Cholesterol in peripheral tissues HDL is produced in liver and intestines as an empty carrier for cholesterol (containing mainly phospholipid and apo A-1) HDL binds to cells in periphery (including in vascular lesions) and takes up surplus cholesterol Cholesterol-laden HDL is taken up into the liver by endocytosis, cholesterol is recycled
Slide 24-

The lecithin-cholesterol acyltransferase (LCAT) reaction
Slide 25-

Cholesterol esters can be stored inside lipoprotein particles
Slide 26-

Bile acids are derived from cholesterol
Slide 27-

Bile acids undergo enterohepatic cycling
Slide 28-

Bile acid cycling involves multiple transport proteins
Slide 29-

A deficient ABCC2 transporter causes Dubin-Johnson syndrome impaired excretion of bile acids → cholesterol precipitates in the bile → bile stones impaired excretion of bilirubin → jaundice impaired excretion of many drugs → potential drug toxicity
Slide 30-

Is atherosclerosis a metabolic disease? … it is important to remember that the best documented initiating factor is still hypercholesterolemia … additional factors should be considered in the context of how they relate to the processes initiated by hypercholesterolemia. Daniel Steinberg, “Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime”, Nature Medicine 8:1211 (2002).
Slide 31-

Macroscopic appearance of atherosclerotic lesions
Slide 32-

Microscopic appearance of atherosclerotic lesions
Slide 33-

Development of an atherosclerotic lesion
Slide 34-

Metabolic aspects of atherosclerosis cholesterol uptake, synthesis and degradation cholesterol transport in the circulation: LDL (low density lipoprotein) and HDL (high density lipoprotein) biochemical changes that turn physiological, benign LDL into an atherogenic agent
Slide 35-

Two modes of uptake of cholesterol into macrophages
Slide 36-

Modification of LDL is essential for excessive uptake by macrophages via the scavenger receptor LDL receptor is down-regulated once the cell is full up with cholesterol—no further LDL will be taken up Covalently modified LDL will be taken up by macrophages via scavenger receptors Various modifications have similar effects Modifications can affect both lipid and apolipoprotein components of LDL
Slide 37-

Experimental protein modifications that turn LDL into a ligand for the scavenger receptor
Slide 38-

Which modifications of LDL are significant in vivo?
Slide 39-

How does LDL become oxidized? Phagocytes produce reactive oxygen species Transition metals (Fe, Cu) exacerbate ROS activity Lipoxygenases convert fatty acids to radicals that can bind to LDL and induce lipid peroxidation
Slide 40-

Self-sustained lipid peroxidation induced by peroxy radicals
Slide 41-

α-Tocopherol intercepts lipid peroxidation
Slide 42-

Experimental evidence implicating LDL oxidation in the pathogenesis of atherosclerosis Vitamin E reduces the severity of atherosclerosis in animal models—but not in clinical studies on humans Antibodies against oxidized LDL are found in blood; among these, IgG promotes atherosclerosis, whereas IgM inhibits it Haptoglobin alleles differ in the efficiency of hemoglobin clearance, which correlates inversely with susceptibility to atherosclerosis Production of HOCl by myeloperoxidase: chlorotyrosine residues detectable in oxLDL ex vivo—but myeloperoxidase k.o. mice have increased susceptibility to atherosclerosis
Slide 43-

Lowering LDL cholesterol: therapeutic principles inhibition of cholesterol synthesis inhibition of cholesterol uptake inhibition of cholesterol ester transfer protein inhibition of bile acid reuptake LDL apheresis
Slide 44-

“Statins” inhibit HMG-CoA reductase
Slide 45-

Inhibitors of intestinal cholesterol uptake
Slide 46-

Cholesterol ester transfer protein (CETP) short-circuits cholesterol transport by lipoproteins
Slide 47-

Cholestyramine particles absorb bile acids
Slide 48-

LDL apheresis Blood is diverted through an extra-corporeal filtration device cells are separated from plasma LDL is removed from plasma by affinity methods or size-based filtration The remaining plasma and cells are returned to the circulation The procedure is repeated in weekly or biweekly intervals
Slide 49-

More … triparanol—an old drug, inhibits some CYP450 enzymes in the conversion from lanosterol to cholesterol; withdrawn due to toxicity bezafibrate—a PPARγ agonist nicotinic acid—activates hormone-sensitive lipase through a G protein coupled receptor named HM74A; 5 likely additional mechanisms probucol and succinobucol—supposedly antioxidants that prevent LDL oxidation, but also cause unrelated changes in other laboratory parameters guar gum and other carbohydrate fibers —absorb and prevent intestinal uptake of cholesterol and bile acids with variable efficiency thyroid hormone analogs—promote LDL utilization
Slide 50-

Familial hypercholesterolemia is due to a gene defect in the LDL receptor
Slide 51-

Tangier disease: Disruption of cholesterol transfer to HDL
Slide 52-

A defective plant sterol exporter causes sitosterolemia