Lipid Transport SOM 610 PDF

1  Phosphatidylinositol Often has stearic acid on carbon 1 and arachidonic acid on carbon 2. Reservoir for arachidonic acid (precursor to prostaglandins). Phosphorylated to make phosphatidyl- inositol 4,5-bisphosphate. Anchors membrane proteins. Located primarily on the inner leafl...

1  Phosphatidylinositol Often has stearic acid on carbon 1 and arachidonic acid on carbon 2. Reservoir for arachidonic acid (precursor to prostaglandins). Phosphorylated to make phosphatidyl- inositol 4,5-bisphosphate. Anchors membrane proteins. Located primarily on the inner leaflet Signal transduction 4  Eicosanoids (signal molecules) Made from 20 carbon fatty acids such as arachidonic acid. Prostaglandins (PG) Thromboxanes (TX) Leukotrienes (LT) “Local” Hormones (short half-life, small amounts made) Autocrine/ Paracrine action (affect cells which produce them or neighboring cells) Inflammatory response Smooth muscle contraction Bronchioconstriction/dilation 5  Eicosanoid Metabolism Arachidonic acid is the precursor to Like cortisol several classes of prostaglandins, thromboxanes and leukotrienes. NSAIDs = nonsteroidal antiinflammatory drugs 6  What is formed next depends upon the type of cell involved. (Tissue specific step) 7  Different tissues vary in the enzymes that convert arachidonic acid to eicosanoids Produce different sets of eicosanoids Illicit different responses PG and TX have very short half-lives Potent effectors of biological functions 8 9 Most of cholesterol synthesized in liver and intestine, some in hormone-producing cells. 10  All 27 carbon atoms of cholesterol are derived from acetyl CoA. Cholesterol biosynthetic enzymes associated with the smooth endoplasmic reticulum. Liver has expanded smooth ER. 11  The synthesis of mevalonate, catalyzed by HMG- CoA reductase, is the committed step in cholesterol formation. Cholesterol HMG-CoA reductase HMG-CoA synthase HMG-CoA cleavage enzyme Ketone Bodies 12 As intracellular cholesterol accumulates: Decreased activity of reductase Decreased translation of mRNA Decreased transcription of gene Increased degradation of enzyme Statins (e.g., lovastatin) lower cholesterol by inhibiting HMG CoA reductase. Regulation of HMG-CoA reductase High insulin, active reductase High glucagon, inactive reductase 14  SREBP-2 is a transcriptional activator of the HMG CoA reductase gene If sterol levels are HIGH, SREBP-2 is sequestered in ER by binding to SCAP and INSIG 15  If sterol levels are LOW, SREBP-2/SCAP moves to Golgi. Proteases release an active form of SREBP-2 Promotes transcription of HMG CoA reductase mRNA. 16  Phosphorylation of HMG CoA reductase INACTIVATES it. Can be done by AMP-activated protein kinase (AMPK) Can also be done by hormone-regulated kinase and phosphatase 17 You don’t need to know all these steps… Ubiquinone 18 Inhibition of HMG CoA reductase can deplete Coenzyme Q Cholesterol is stored intracellularly in an ester linkage to a fatty acid - cholesteryl ester. More hydrophobic. Intracellular enzyme is ACAT - Acyl-CoA:cholesterol acyltransferase In blood - PCAT or LCAT 20 Bile Salts/Bile Acids 7a-hydroxylase is committed step in bile salt/acid synthesis in liver 21 Bile acids conjugated to glycine or taurine. Results in formation of primary bile salts. Conjugated bile salts have lower pK values - more easily ionized. More amphipathic - better detergents. Secreted into bile and stored in gall bladder. 22 Secondary bile salts/acids Deconjugated and de- hydroxylated (at C-7) by intestinal bacteria Less soluble - less readily resorbed 23 Bile salts/acids reabsorbed with > 95% efficiency. Only way to get rid of excess cholesterol is by excretion of bile salts/acids! 24 What happens when cholesterol concentration in bile greatly exceeds that of bile salts? Malabsorption of bile salts/acids Obstruction of biliary tract Hepatic dysfunction Excessive feedback suppression of bile acid synthesis 25 September 29, 2001