1 / 59

Cholesterol Metabolism

Cholesterol Metabolism. Objectives. Define cholesterol as the most important animal steroid. Know The structure of cholesterol. Discuss the Synthesis of cholesterol. Identify the Regulation of cholesterol. Describe the Excretion of cholesterol. Define Hypercholesterolemia.

gabrielle-moreau
Télécharger la présentation

Cholesterol Metabolism

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Cholesterol Metabolism

  2. Objectives • Define cholesterol as the most important animal steroid. • Know The structure of cholesterol. • Discuss the Synthesis of cholesterol. • Identify the Regulation of cholesterol. • Describe the Excretion of cholesterol. • Define Hypercholesterolemia.

  3. CHOLESTEROL METABOLISM Overview: • Cholesterol is the most important animal steroid • Brain & egg yolk is very rich sources. The liver, kidney and red meat are rich sources. • Average diet supplies about 0.5 - 1 g /day.

  4. Cholesterol is an extremely important biological molecule that has roles in membrane structure as well as being a precursor for the synthesis of thesteroidhormones and bile acids and vit D3 Both dietary cholesterol and that synthesized de novo are transported through the circulation in lipoprotein particles. The same is true of cholesteryl esters, the form in which cholesterol is stored in cells.

  5. The synthesis and utilization of cholesterol must be tightly regulated in order to prevent over-accumulation and abnormal deposition within the body Such deposition, eventually leading to atherosclerosis, is the leading contributory factor in diseases of the coronary arteries.

  6. Mostplasma cholesterol is in an esterified form , w is more hydropobicthan free cholesterol. Cholesteryl esters (CE) are not found in membranes CE are normally present in low levels in most cells Choesterol & CE must be transported in association with protein in LP or solubilized by phospholipids and bile salts in the bile

  7. Cholesterol: is a sterol (with 8 carbons at C17,= bet 5&6) • Sterols:are steroids with 8-10 carbon atoms in the side chain at C-17 & OH at C-3 • Cholesterol is themajor sterol in animal tissues • Plant sterols as B-sitosterol are poorly absorbed by humans, it blocks the absorption of dietary cholesterol • Dietary intake of plant steroid esters (trans fatty acid –free margarine ) helps in reduction of plasma cholesterol

  8. Structure of cholesterol and its ester. Plant sterols block the absorption of dietary cholesterol.

  9. PLASMACHOLESTEROL • Plasma cholesterol level is 150 – 200 mg/dl (average 175 mg/dl) • Types: 30% of plasma cholesterol are free and 70% are esterified with polyunsaturated fatty acids (PUFA)

  10. Biosynthesis of Cholesterol

  11. Cholesterol synthesis by all tissues esp.: liver, intestine ,adrenal cortex,& reproductive tissues It occurs in the cytoplasm with enzymes in both the cytosol and the membrane of the endoplasmic reticulum Synthesis begins with the transport of acetyl-CoA from the mitochondrion to the cytosol It needs reducing equivalents in form NADPH & energy from hydrolysisof the high-energy thioesterbond of acetyl CoA

  12. The rate limiting step occurs at the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, HMGR catalyzed step. • The phosphorylation reactions are required to solubilize the intermediates in the pathway. • After dephosphorylation the intermediates require intracellular sterol carrier protein to keep them soluble • Release of pyrophosphate in the condensation steps make the reactions irreversible

  13. Liver parenchymal cells contain two isoenzymes of HMGCoAsynthhaseThe cytolsolic enzyme participates in cholesterol synthesis & the mitochondrial enzyme for ketone bodies synthesisHMGCoA synthase is an intrinsic membrane protein of the endoplasmic reticulum with the enzyme catalytic domain projecting into the cytosol

  14. 6C 5C C30 to C27 Removal of CH3 at C4 = migration from C8 to C5 Reduction of= bet C24&C25 10C 15C NADPH NADP Squalene synthase O2+NADPH+H Cyclization CYCLE 1ST 27C Squalene monooxygenase

  15. Regulationof Cholesterol Synthesis

  16. 1.Sterol-dependent regulation of gene expression:↑Cholesterol – transcription factor 2.Sterol-independent phosphorylation/dephosphorylation 3.Hormonal regulation 4.Inhibition by drugs: simvastatin, lovastatin &mevastatin

  17. Cholesterol Degradation Ring of sterol can’t be metabolized to CO2 & H2O in humans Secretion as such in bile Conversion to bile acids Intest. Egested as such Modified by bacteria by reduction Coprostanol & cholestanol isomers )( Neutral sterols

  18. Bile acids &salts Bile consists of org. & inorg. watery mixture Lecithin & bile salts are the most important org .quantitatively Bile liver duodenum stored in GB Bile salts are more effective detergents than bile acids b/c of their enhanced amphipathic structure

  19. HYPERCHOLESTEROLEMIA • It is the increase of plasma cholesterol above 220 mg/dl. • Hypercholesterolemia is associated with atherosclerosis, coronary heart disease (CHD), heart attacks, and stroke • Causes: 1) Overfeeding of diet rich in cholesterol, Fats specially saturated FA ,or carbohydrates 2) Diabetes mellitus (D.M.) 3) Hypothyroidism: due to decreased conversion to bile acids 4) Obstructive jaundice: due to the obstruction no excretion of cholesterol or bile salts in the bile 5) Familial hypercholesterolemia

  20. Treatment of Hypercholesterolemia • 1- Diet: Decrease carbohydrate, saturated fatty acids and cholesterol in diet. Increase polyunsaturated fatty acids • 2- Hypocholesterolemic drugs: Statin drugs e.g. • Atorvastatin (Lipitor) and simvastatin (Zocor) are used to decrease plasma cholesterol levels in patients with hypercholesterolemia • Statin drugs are competitive inhibitors of HMG CoA reductase

  21. LipoproteinsMetabolism

  22. Introduction Lipid compounds: Relatively water insoluble Therefore, they are transported in plasma (aqueous) asLipoproteins

  23. Lipoproteins and Related Clinical Problems Atherosclerosis and hypertension Coronary heart diseases Lipoproteinemias (hypo- and hyper-) Fatty liver

  24. Lipoprotein Structure • Protein part: Apoproteins or apolipoproteins • These proteins may be structural or transferred • Lipid part: • According to the type of lipoproteins • Different lipid components in various combinations

  25. Spherical molecules of lipids and proteins (apoproteins) = amphipathic molecules Outer coat: - Apoproteins - Phospholipids - Cholesterol (Unesterified) Inner core: - TG - Cholesterol ester (CE) Lipoprotein Structure

  26. Apoproteins Five major classes (A-E) divided by structure & function Each class has subclasses as Apo A1, Apo CII Functions Some are required as structural proteins Some are activators, Some are recognition sites.

  27. Types of Lipoproteins There are various types of lipoproteins: They differ in lipid and protein composition and therefore, they differ in: - Size and density - Electrophoretic mobility

  28. Chylomicrons Very low density Lipoprotein (VLDL) Low density Lipoprotein (LDL) High density Lipoprotein (HDL) Types and Composition of Lipoproteins

  29. Composition of LDL and HDL Low density lipoprotein (LDL) Mostly free cholesterol • High density lipoprotein (HDL) • Mostly cholesterol ester • More % protein • More % phospholipids

  30. Ultracentrifugation of Lipoproteins

  31. Lipoprotein Electrophoresis

  32. Plasma Lipoproteins • For triacylglycerol transport (TG-rich): • - Chylomicrons:TG ofdietary origin • - VLDL: TG ofendogenous (hepatic) synthesis • For cholesterol transport (cholesterol-rich): • LDL: Mainly free cholesterol • HDL: Mainly esterified cholesterol

  33. Chylomicrons Assembled in intestinal mucosal cells Lowest density Largest size Highest % of lipids and lowest % proteins Highest triacylglycerol (dietary origin) Carry dietary lipids to peripheral tissues Responsible for physiological milky appearance of plasma (up to 2 hours after meal)

  34. Type I hyperlipoprotemia Apo E mediates uptake

  35. Lipoprotein Lipase Extracellular enzyme anchored by heparan sulphate to the capillary walls of most tissue esp those of adipose tissue, cardiac & skeletal muscles Its synthesis & transfer to luminal surface of the capillary is stimulated by insulin Activated by apoC-II

  36. Isomers of lipoprotein lipase have different kms for TAG :high km in the adipose enzyme • Low km in the heart enzymes • is absent in adult liver which has hepatic lipase on the endothelial surface which assists in HDL metabolism mainly

  37. Metabolism of VLDL

  38. VLDL CE PL ,TAG HDL Choleteryl Ester Transfer Protein

  39. Composition of LDL and HDL Low density lipoprotein (LDL) Mostly free cholesterol • High density lipoprotein (HDL) • Mostly cholesterol ester • More % protein • More % phospholipids

  40. Low Density Lipoprotein LDL carries about 70% of total plasma cholesterol High LDL-C level is well established risk factor for development of coronary heart disease The diagnosis of a primary defect is made after secondary defect causes have been ruled out

  41. Low Density Lipoproteins (LDL) Produced in the circulation as the end product of VLDLs Compared to VLDLs: It contains only apo B-100 Smaller size and more dense Less TG More cholesterol & cholesterol ester Transport cholesterol from liver to peripheral tissues Uptake of LDL at tissue level by LDL receptor-mediated endocytosis Recognized by apo B-100

  42. LDL: Receptor-Mediated Endocytosis

  43. Receptor-Mediated Endocytosis LDL receptor:Cell surface glycoprotein High-affinity, tightly regulated LDL/Receptor binding and internalization of the complex by endocytosis Release of cholesterol inside the cells for:Utilization Storage as cholesterol ester Excretion Degradation of LDL:into amino acids, phospholipids and fatty acids Degradation or recycling of receptor

  44. LDL Receptor-Mediated Endocytosis: Regulation Down-regulation:High intracellular cholesterol contentDegradation of LDL receptors Inhibition of recepotor synthesis at gene levelDecrease No. of receptor at cell surfaceDecrease further uptake of LDL Decrease de novo synthesis of cholesterol Up-regulation: Low intracellular cholesterol content Recycling of LDL receptors Stimulation of recepotor synthesis at gene level Increase No. of receptor at cell surfaceIncrease further uptake of LDL Increase de novo synthesis of cholesterol

  45. Plasma LDL can be measured by ultracentrifugation, but this is not a practical technique Calculated LDL: LDL-C= total cholesterol –[HDL-C]+ TAG/2.2) in case of mmol/L or 5 in case of mg/dL LDL exits in a range of sizes & densities which can be detected by electrophoresis. There is evidence that small dense LDL is atherogenic

More Related