Cholesterol Metabolism PDF

Cholesterol Metabolism Dr. Zahraa K mohammed  Objectives Understand the structure and functions of cholesterol Discuss the regulation of cholesterol homeostasis in the body Comprehend the important steps of cholesterol synthesis pathway Identify different levels of regu...

Cholesterol Metabolism Dr. Zahraa K mohammed  Objectives Understand the structure and functions of cholesterol Discuss the regulation of cholesterol homeostasis in the body Comprehend the important steps of cholesterol synthesis pathway Identify different levels of regulation of cholesterol synthesis Discuss the association of hypercholesterolemia with abnormal cholesterol metabolism Understand the role of statins in the treatment of hypercholesterolemia  Cholesterol Most important animal steroid Maintains membrane fluidity Insulating effect on nerve fibres Cholesterol is the parent molecule for Bile acids and bile salts Steroid hormones Vitamin D3  Liver plays a central role in the regulation of cholesterol homeostasis Cholesterol Structure  Cholesteryl esters Most plasma cholesterol is esterified with a fatty acid CEs are not present in membranes Present in small amounts in most cells More hydrophobic than cholesterol  Cholesterol synthesis Synthesized in all tissues Major sites for synthesis: liver, adrenal cortex, testes, ovaries and intestine All carbon atoms are derived from acetyl CoA Enzymes involved in biosynthesis are partly located in ER and partly in cytoplasm Synthesis of HMG CoA HMG CoA is present in both cytosol and mitochondria of liver Mitochondrial-ketogenesis Cytosolic – cholesterol synthesis  Synthesis of mevalonic acid Rate limiting and key step Occurs in cytosol HMG CoA reductase is an ER membrane enzyme with catalytic unit hanging in the cytosol Further steps in synthesis Regulation of Cholesterol Synthesis HMG CoA reductase is the rate-limiting enzyme of cholesterol synthesis  HMG CoA Reductase Regulation Sterol-dependent regulation of gene expression Sterol-independent phosphorylation/dephosphorylation Hormonal regulation  Sterol-dependent regulation of gene expression of HMG CoA When sufficient cholesterol is present, transcription is suppressed and vice versa Sterol Regulatory Element (SRE) is a recognition sequence in the DNA SREBP (SRE binding protein) binding to SRE is essential for transcription of this gene SREBP cleavage-activating protein (SCAP) is an intracellular cholesterol sensor Enzyme phosphorylation and dephosphorylation AMP- activated protein kinase (AMPK) for phosphorylation Phosphorylated form of enzyme is inactive Dephosphorylated form is active High AMP  cholesterol synthesis decreases  Hormonal Regulation Insulinand thyroxine increase upregulation of enzyme expression Glucagon and cortisol have opposite effect HMG CoA Reductase Regulation Gene Cholesterol Transcription Translation Insulin HMG CoA Reductase Glucagon Thyroxin Cortisol Statins HMG CoA Cholesterol  Excretion of cholesterol By conversion into bile acids and bile salts- excreted in the feces Secretion of cholesterol in bile Transported to intestine for elimination In the intestine, some cholesterol is converted by bacteria into coprostanol and cholestanol before excretion  Hypercholesterolemia High conc. of cholesterol in blood Leads to atherosclerosis Statin drugs are used to decrease plasma cholesterol levels Statins are structural analogs of HMG CoA reductase Statins inhibit enzyme activity by competitive inhibition -Sitosterols/ Phytosterols Plant sterols are poorly absorbed by humans Block the absorption of dietary cholesterol Clinically useful in the dietary treatment of hypercholesterolemia  Bile Acids Cholesterol is oxidize in the liver variety of bile acids. These, in turn, are conj with glycine, taurine, and glucuronic A mixture of conjugated and non conjugated bile acids, along with cholesterol itself, is excreted from the liver into the bile Approximately 95% of the bile acids are reabsorbed from the intestine, and the remainder are lost in the fece  Bile salt deficiency: cholelithiasis It is the precipitation of cholesterol in the gallbladder leading to cholesterol gallstone disease (due to a decrease of bile acids in the bile or due to increased biliary cholesterol excretion as in the use of fibrates drug)