{"id":4422560,"date":"2025-01-12T05:38:49","date_gmt":"2025-01-12T11:38:49","guid":{"rendered":"https:\/\/myendoconsult.com\/learn\/topics\/cholesterol-metabolism\/"},"modified":"2025-01-12T05:41:49","modified_gmt":"2025-01-12T11:41:49","slug":"cholesterol-metabolism","status":"publish","type":"oen_topic","link":"https:\/\/myendoconsult.com\/learn\/topics\/cholesterol-metabolism\/","title":{"rendered":"Cholesterol Metabolism"},"content":{"rendered":"\n<h2 class=\"wp-block-heading\">CHOLESTEROL SYNTHESIS AND METABOLISM<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">Structure and Roles of Cholesterol<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>4-ring hydrocarbon structure<\/strong> with an 8-carbon side chain.<\/li>\n\n\n\n<li>Key component of <strong>cell membranes<\/strong>.<\/li>\n\n\n\n<li>Substrate for <strong>steroid hormones<\/strong> and <strong>bile acids<\/strong>.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Sources of Cholesterol<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Endogenous synthesis<\/strong> in the liver and other tissues.<\/li>\n\n\n\n<li><strong>Exogenous ingestion<\/strong> of animal fats (e.g., meat, eggs, dairy).<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Biosynthesis Pathway<\/h3>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Acetate condensation<\/strong>: Three molecules of acetate \u2192 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA).<\/li>\n\n\n\n<li><strong>Rate-limiting step<\/strong>: HMG-CoA \u2192 mevalonic acid, catalyzed by <strong>HMG-CoA reductase<\/strong>.\n<ul class=\"wp-block-list\">\n<li><strong>Statins<\/strong> (HMG-CoA reductase inhibitors) \u2193 cholesterol biosynthesis \u2192 \u2193 serum cholesterol.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Mevalonic acid<\/strong> \u2192 <strong>cholesterol<\/strong> through multiple enzymatic steps.<\/li>\n<\/ol>\n\n\n\n<h3 class=\"wp-block-heading\">Cholesterol Metabolism and Excretion<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Excreted into the bile as <strong>free cholesterol<\/strong> or converted to <strong>bile acids<\/strong>.<\/li>\n\n\n\n<li><strong>Enterohepatic circulation<\/strong>:\n<ul class=\"wp-block-list\">\n<li>~50% of biliary cholesterol and ~97% of bile acids are reabsorbed in the small intestine and returned to the liver.<\/li>\n\n\n\n<li>The remainder is <strong>excreted in feces<\/strong>.<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">LIPOPROTEIN OVERVIEW<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">Composition<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Macromolecules containing:\n<ul class=\"wp-block-list\">\n<li><strong>Protein<\/strong> (apolipoproteins, \u201capo\u201d),<\/li>\n\n\n\n<li><strong>Triglycerides<\/strong>,<\/li>\n\n\n\n<li><strong>Cholesterol esters<\/strong>,<\/li>\n\n\n\n<li><strong>Free cholesterol<\/strong>.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li>Function: <strong>Transport<\/strong> dietary and endogenous lipids (cholesterol, triglycerides) in the blood.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Classes of Lipoproteins<\/h3>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Chylomicrons<\/strong>\n<ul class=\"wp-block-list\">\n<li>Large, low-density particles carrying <strong>dietary lipid<\/strong>.<\/li>\n\n\n\n<li>Apolipoproteins: apo A (I, II, IV), apo B48, apo C (I, II, III), apo E.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Very Low-Density Lipoprotein (VLDL)<\/strong>\n<ul class=\"wp-block-list\">\n<li>Mainly transports <strong>triglycerides<\/strong>.<\/li>\n\n\n\n<li>Apolipoproteins: apo B100, apo C (I, II, III), apo E.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Low-Density Lipoprotein (LDL)<\/strong>\n<ul class=\"wp-block-list\">\n<li>Transports primarily <strong>cholesterol esters<\/strong>.<\/li>\n\n\n\n<li>Apolipoprotein: <strong>apo B100<\/strong>.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>High-Density Lipoprotein (HDL)<\/strong>\n<ul class=\"wp-block-list\">\n<li>Transports mainly <strong>cholesterol esters<\/strong>.<\/li>\n\n\n\n<li>Apolipoproteins: apo A (I, II), apo C (I, II, III), apo E.<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n\n\n\n<h3 class=\"wp-block-heading\">Apolipoprotein Functions<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>apo AI<\/strong>: Structural protein of HDL, activates LCAT (lecithin\u2013cholesterol acyltransferase).<\/li>\n\n\n\n<li><strong>apo AII<\/strong>: Structural protein of HDL, activates hepatic lipase.<\/li>\n\n\n\n<li><strong>apo AIV<\/strong>: Activator for lipoprotein lipase (LPL) and LCAT.<\/li>\n\n\n\n<li><strong>apo B100<\/strong>: Structural protein for VLDL and LDL; ligand for LDL receptor.<\/li>\n\n\n\n<li><strong>apo B48<\/strong>: Required for <strong>chylomicron<\/strong> formation and secretion.<\/li>\n\n\n\n<li><strong>apo CI<\/strong>: Activates LCAT.<\/li>\n\n\n\n<li><strong>apo CII<\/strong>: <strong>Key cofactor for LPL<\/strong> (triglyceride hydrolysis).<\/li>\n\n\n\n<li><strong>apo CIII<\/strong>: Inhibits LPL.<\/li>\n\n\n\n<li><strong>apo E<\/strong>: Ligand for VLDL\/chylomicron remnant receptor; three isoforms (E2, E3, E4). Homozygous E2 \u2192 familial dysbetalipoproteinemia (<a href=\"https:\/\/myendoconsult.com\/learn\/types-of-hyperlipidemia\/\"  data-wpil-monitor-id=\"278\">Type III hyperlipidemia<\/a>).<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">LDL Receptor and Cholesterol Homeostasis<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>LDL receptor <strong>mediates endocytosis<\/strong> of apo B\u2013 or apo E\u2013containing lipoproteins (LDL, chylomicron remnants, VLDL).<\/li>\n\n\n\n<li><strong>LDL receptor expression<\/strong> is regulated based on <strong>cellular cholesterol<\/strong> levels.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">GASTROINTESTINAL ABSORPTION OF CHOLESTEROL AND TRIGLYCERIDES<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">Dietary Fat Digestion<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Starts in <strong>stomach<\/strong> (gastric peristalsis, mixing, gastric lipase).<\/li>\n\n\n\n<li>Primarily completed in the <strong>small intestine<\/strong>.<\/li>\n\n\n\n<li><strong>Triglycerides<\/strong> \u2192 free fatty acids + monoglycerides by <strong>pancreatic lipase<\/strong>.<\/li>\n\n\n\n<li><strong>Bile salts<\/strong> form micelles \u2192 facilitate transport to enterocytes.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Enterocyte Uptake and Chylomicron Formation<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Long-chain fatty acids<\/strong> re-esterified into triglycerides in smooth ER.<\/li>\n\n\n\n<li>Cholesterol esterified by <strong>cholesterol acyltransferase<\/strong>.<\/li>\n\n\n\n<li>Assembly with apo proteins (apo B48) \u2192 <strong>chylomicrons<\/strong> in the Golgi.<\/li>\n\n\n\n<li>Chylomicrons exit enterocytes \u2192 <strong>lymphatics<\/strong> \u2192 <strong>thoracic duct<\/strong> \u2192 <strong>bloodstream<\/strong>.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Intravascular Metabolism<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Chylomicrons obtain <strong>apo C<\/strong> and <strong>apo E<\/strong> in circulation.<\/li>\n\n\n\n<li><strong>Lipoprotein lipase (LPL)<\/strong> in muscle\/adipose\/breast tissue breaks down chylomicron triglycerides.<\/li>\n\n\n\n<li>Remnants taken up by <strong>liver<\/strong> via apo E recognition.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">REGULATION OF LDL RECEPTOR AND CHOLESTEROL CONTENT<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">Key Points<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Plasma <strong>LDL<\/strong> (cholesterol) mainly cleared by the <strong>LDL receptor<\/strong>.<\/li>\n\n\n\n<li>~75% of LDL uptake occurs in the <strong>liver<\/strong>.<\/li>\n\n\n\n<li><strong>Sterol regulatory element\u2013binding protein (SREBP)<\/strong> modulates LDL receptor gene expression and HMG-CoA reductase.<\/li>\n\n\n\n<li>Intracellular cholesterol up \u2192 \u2193 LDL receptors, \u2193 HMG-CoA reductase, \u2191 cholesterol storage via ACAT.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Common Genetic Dyslipidemias<\/h3>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Familial Hypercholesterolemia (FH)<\/strong>\n<ul class=\"wp-block-list\">\n<li>Autosomal dominant, LDL receptor mutations.<\/li>\n\n\n\n<li>\u2191 plasma <a href=\"https:\/\/myendoconsult.com\/learn\/what-is-ldl-cholesterol\/\"  data-wpil-monitor-id=\"279\">LDL cholesterol<\/a>, \u2191 CHD risk.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Familial Defective apo B100<\/strong>\n<ul class=\"wp-block-list\">\n<li>apo B100 mutation \u2192 defective LDL receptor binding \u2192 \u2191 LDL.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Familial Dysbetalipoproteinemia (Type III)<\/strong>\n<ul class=\"wp-block-list\">\n<li>apo E2\/E2 \u2192 defective chylomicron\/VLDL remnant clearance \u2192 \u2191 cholesterol + \u2191 triglycerides.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Elevated Lipoprotein(a)<\/strong>\n<ul class=\"wp-block-list\">\n<li>Covalent bond of apo B100 to Lp(a), impairs fibrinolysis \u2192 \u2191 CHD risk.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Polygenic Hypercholesterolemia<\/strong>\n<ul class=\"wp-block-list\">\n<li>Multiple genetic\/environmental factors, borderline-high or high LDL, increased CHD risk.<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">HIGH-DENSITY LIPOPROTEIN METABOLISM AND REVERSE CHOLESTEROL TRANSPORT<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">HDL Structure<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Composed of ~50% lipid (phospholipids, cholesteryl esters, free cholesterol, triglycerides) + ~50% protein (apo AI, apo AII, others).<\/li>\n\n\n\n<li>Main <strong>subclasses<\/strong>: HDL2, HDL3, minor HDL1.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Reverse Cholesterol Transport<\/h3>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Nascent\/precursor HDL<\/strong> (apo AI, phospholipids) formed in liver\/intestine.<\/li>\n\n\n\n<li>HDL <strong>accepts free cholesterol<\/strong> from cells or TGRLs (chylomicrons, VLDL).<\/li>\n\n\n\n<li><strong>LCAT<\/strong> (activated by apo AI) esterifies free cholesterol \u2192 cholesteryl esters \u2192 moves to HDL core \u2192 HDL2 forms.<\/li>\n\n\n\n<li><strong>Cholesteryl ester transfer protein (CETP)<\/strong> exchanges cholesteryl esters in HDL2 for triglycerides in TGRLs.<\/li>\n\n\n\n<li>Depleted HDL2 can become HDL3 via <strong>hepatic lipase<\/strong> hydrolysis of extra triglycerides.<\/li>\n\n\n\n<li><strong>SR-B1<\/strong> (scavenger receptor B1) mediates selective uptake of cholesteryl esters into adrenal, gonadal, liver cells.<\/li>\n<\/ol>\n\n\n\n<h3 class=\"wp-block-heading\">Clinical Relevance<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>HDL is <strong>antiatherogenic<\/strong>:\n<ul class=\"wp-block-list\">\n<li>Removes cholesterol from cells (incl. arterial walls).<\/li>\n\n\n\n<li>Paraoxonase enzyme on HDL inhibits LDL oxidation.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Inversely<\/strong> correlated with <strong>CHD risk<\/strong> (higher HDL = lower risk).<\/li>\n\n\n\n<li><strong>Tangier disease<\/strong>: ABCA1 mutation \u2192 low HDL due to poor free cholesterol\/phospholipid transfer to apo AI.<\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"<p>CHOLESTEROL SYNTHESIS AND METABOLISM Structure and Roles of Cholesterol Sources of Cholesterol Biosynthesis Pathway Cholesterol Metabolism and Excretion LIPOPROTEIN OVERVIEW Composition Classes of Lipoproteins&hellip;<\/p>\n","protected":false},"featured_media":0,"template":"","oen_topic_chapter":[688],"class_list":["post-4422560","oen_topic","type-oen_topic","status-publish","hentry","oen_topic_chapter-lipid-metabolism"],"_links":{"self":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic\/4422560","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic"}],"about":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/types\/oen_topic"}],"version-history":[{"count":3,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic\/4422560\/revisions"}],"predecessor-version":[{"id":4422563,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic\/4422560\/revisions\/4422563"}],"wp:attachment":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/media?parent=4422560"}],"wp:term":[{"taxonomy":"oen_topic_chapter","embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic_chapter?post=4422560"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}