5.初级版课件3english vesion英文版-abridgedmetabolism

1、Chapter30 Cholesterol metabolismOutlineBiosynthesis of CholesterolTransport of CholesterolConversion of CholesterolRegulation of Cholesterol MetabolismTop four reasons we need cholesterolMembrane component- controls fluidityPrecursor of bile acids and bile saltsPrecursor of steroid hormonesPrecursor

2、 of vitamin DSterols galore!Structure of cholesterolSite of attachment of fatty acid in cholesterol esterCholesterol biosynthesisPrecursor for cholesterol biosynthesis-acetyl CoAAlso requires NADPH and ATPFour-stage reaction: Acetate (C2) Isoprenoid (C5) Squalene (30) Cholesterol (27)Highly regulate

3、d processOccurs in the cytoplasmEndoplasmic reticulumCytosolFour stages of cholesterol synthesisAcetyl CoA to Isopentenyl DiphosphateSynthesis of mevalonateConversion to activated isoprenesHMG-CoA reductaseIntegral membrane protein in the ERCarries out an irreversible reaction Is an important regula

4、tory enzyme in cholesterol synthesisCondensation of isoprenesHead to tailIsoprenoids galore!Further condensation of isoprenesAnd even more condensation of isoprenesFrom squalene to cholesterolCholesterol trafficking/deliveryPlasma lipoproteins carry cholesterol and other lipids (triacylglycerols) th

5、roughout the bodyPlasma lipoproteins=lipids + ApolipoproteinsChylomicrons-CM (Intestine)Very Low Density Lipoprotein-VLDL (Liver)IDL (intermediate density lipoprotein)Low Density Lipoprotein-LDLHigh Density Lipoprotein-HDL VLDL IDL LDLApolipoproteins“apo” = lipid-free form of the proteinspecific lip

6、id/ cholesterol carrier proteins that allow distribution of cholesterol and various lipids through blood systeminteract with specific receptors and/or modulate enzyme activity9 different apolipoproteins in humansApolipoprotein functionsFour types of lipoproteins under microscopeLow-density lipoprote

7、in (LDL)Derived from VLDLs upon loss of triacylglycerolsvery rich in cholesterol & cholesteryl esterstransport of cholesterol and their esters to extrahepatic tissuesapoB-100 receptor mediated uptakeassociated apolipoproteins-predominantly apoB-100: (LDL : the infamous lipoproteinReceptor-mediated L

8、DL endocytosisapoB-100 binds to LDL receptorreceptor binding triggers endocytosis and formation of endosome endosome fuses with lysosomedigestion of LDL liposome and relocation of receptor to the surface The role of LDL and HDL in cholesterol metabolismHigh-density lipoprotein (HDL)synthesis of HDL

9、begins in the liver and small intestinecontains the enzyme lecithin-cholesterol acyl transferase (LCAT) = formation of cholesteryl esters from lecithin + cholesterolreturns to the liver where it unloads the cholesterol, some of which is then turned into bile saltstaken up in the liver via receptor m

10、ediated endocytosisalso binds to SR-BI receptors in hepatic tissues and adrenal gland = partial transfer of cholesterol: )HMG-CoA Reductase, the rate-limiting step on the pathway for synthesis of cholesterol, is a major control point. Short-term regulation: -HMG-CoA Reductase is inhibited by phospho

11、rylation, catalyzed by AMP-activated Protein Kinase. -This kinase is active when cellular AMP is high, corresponding to when ATP is low. When AMP is high, why waste energy on cholesterol synthesis?Long-term regulation is by varied transcription and degradation of HMG-CoA Reductase and other enzymes

12、of the pathway for synthesis of cholesterol.Regulation of Cholesterol Synthesis Regulationof cholesterol metabolismboth uptake and synthesis are involvedLong-term regulation IRegulated proteolysis of HMG-CoA Reductase: Degradation of HMG-CoA Reductase is stimulated by cholesterol, oxidized derivativ

13、es of cholesterol, mevalonate, & farnesol (dephosphorylated farnesyl pyrophosphate). HMG-CoA Reductase includes a transmembrane sterol-sensing domain that has a role in activating degradation of the enzyme via the proteasome (proteasome to be discussed later).Long-term regulation IIRegulated transcr

14、iption: A transcription factor SREBP-2 (sterol regulatory element binding protein #2) responds to cellular levels of sterols. (The related SREBP-1 has a role in regulating fatty acid synthesis.) When sterol levels are low, SREBP-2 is released by cleavage of a precursor protein found in endoplasmic r

15、eticulum membranes. A cytosolic domain cleaved from the SREBP precursor protein then translocates into the nucleus where it functions as a transcription factor to activate transcription of genes for HMG-CoA Reductase and other enzymes of the pathway for cholesterol synthesis. Three other proteins ar

16、e involved in the activation of SREBP-2 in response to sterol levelsSCAP (SREBP cleavage-activating protein) - An integral protein of ER membranes that has a transmembrane sterol-sensing domain homologous to that of HMG-CoA Reductase. -SCAP is inhibited by binding of sterols. -When sterol levels are

17、 low, SCAP binds and transports the SREBP precursor protein from the endoplasmic reticulum to the golgi apparatus.Protease S1P (site one protease), an integral protein of golgi membranes, cleaves the SREBP precursor at a particular sitein the lumenal domain. Protease S2P then cleaves within a trans-

18、membrane segment of the SREBP precursor, releasing to the cytosol the N-terminal SREBP domain that functions as a transcription factor.SREBP cleavageactivating proteinSite 1 and site 2 protease - Degradation of cholesterolRing structure not metabolizedCholesterol eliminated by two means:Conversion to bile acids (excreted in feces)Secretion into bile (transport to intestine) Cholesterol and heart diseaseHeart disease is the #1 killer in the USAExcess cholesterol (LDL) in the blood