{"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 Apolipoprotein Functions LDL Receptor and Cholesterol Homeostasis GASTROINTESTINAL ABSORPTION OF CHOLESTEROL AND TRIGLYCERIDES Dietary Fat Digestion Enterocyte Uptake and Chylomicron Formation Intravascular Metabolism REGULATION OF LDL RECEPTOR AND CHOLESTEROL CONTENT Key [&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","post-wrapper","thrv_wrapper"],"_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}]}}