* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Chapter 18
Endogenous retrovirus wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
Gene expression wikipedia , lookup
Secreted frizzled-related protein 1 wikipedia , lookup
Magnesium transporter wikipedia , lookup
Endocannabinoid system wikipedia , lookup
Expression vector wikipedia , lookup
Biochemistry wikipedia , lookup
Gene regulatory network wikipedia , lookup
Clinical neurochemistry wikipedia , lookup
Proteolysis wikipedia , lookup
Human digestive system wikipedia , lookup
Lipid signaling wikipedia , lookup
Biochemical cascade wikipedia , lookup
Fatty acid metabolism wikipedia , lookup
G protein–coupled receptor wikipedia , lookup
Paracrine signalling wikipedia , lookup
Gene expression profiling wikipedia , lookup
Multiple SREBPs regulate expression of numerous lipid-metabolizing proteins Fatty acid metabolism Chosterol metabolism SREBP also regulated NADPH activity Chapter 18 Part II Low cholesterol→ cell → SREBPs activation → turn on gene A. Normal/High cellular free cholesterol Protease is inhibited B. ER ER Sterol Regulatory Element Binding Protein trapped in ER as precursor X Low cellular free cholesterol protease is active to cleave pre-SREBP-1 ER NUCLEUS Repressed Genes Repressed Genes: 1. HMG CoA reductase 2. LDL receptor Transcriptional Activation Nucleus Induced Genes: 1. HMG CoA reductase 2. LDL receptor Promoter Region Promoter Region pre-SREBP-1 SREBP-1 protease pre-SREBP-1 Figure 3. Regulation of HMG CoA reductase by repression SREBP-1 Figure 3. Regulation of HMG CoA reductase by induction protease 1 Member of the nuclear receptor superfamily contribute to cellular an whole body lipid regulation ABC proteins mediate cellular export of phospholipids and cholesterol SREBP regulated cholesterol and lipid metab Other hydrphobic molecular (steroid hormone) enter cytosol → nuclear receptor → regulated related gene expression In liver: Cholesterol ↑↑ → produce oxysterol → activated LXR (liver X receptor) → cholesterol 7α-hydroxylase → (cholesterol convent to) bile acid → secret excessive cholesterol LXR → stimulated ABC expression (ABCG5/8; ABCA1) → cholesterol release LXR → SREBP activation → lipid synthesis related enzyme expression LXR sense massive cholesterol Bile acid bind to FXR (nuclear receptor) → activation of FXR → I-BABP, ABCB11, NTCP expression ; inhibited cholesterol 7α-hydroxylase Na-linked symporter (NTCP) 95% Binding protein IBAT: ileal bile acid transporter (IBAT) I-BABP: intenstinal bile acid-binding protein Fig 18-11 Major transport proteins in the liver and intestine taking part in the enterohepatic circulation of biliary lipids Role of LXR and FXR When cholesterol accumulates in cells, cholesterol is oxidized to create oxysterols 2 Role of LXR and FXR Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis Role of LXR and FXR Role of LXR and FXR In the intestine, LXR also activates ABC-1 to remove cholesterol 18.5 The cell biology of atherosclerosis, heart attacks, and strokes In the intestine, FXR activates expression of IBABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. 3 Endothelial Dysfunction Increased endothelial permeability to lipoproteins and plasma constituents mediated by NO, PDGF, AG-II, endothelin. Up-regulation of leukocyte adhesion molecules (L-selectin, integrins, etc). Up-regulation of endothelial adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1). Migration of leukocytes into artery wall mediated by oxLDL, MCP1, IL-8, PDGF, M-CSF. Formation of Fatty Streak SMC migration stimulated by PDGF, FGF-2, TGF-B T-Cell activation mediated by TNF-a, IL-2, GM-CSF. Foam-cell formation mediated by oxLDL, TNF-a, IL-1,and M-CSF. Platelet adherence and aggregation stimulated by integrins, P-selectin, fibrin, TXA2, and TF. Ross, NEJM; 1999 Formation of Advanced, Complicated Lesion Fibrous cap forms in response to injury to wall off lesion from lumen. Fibrous cap covers a mixture of leukocytes, lipid and debris which may form a necrotic core. Lesions expand at shoulders by means of continued leukocyte adhesion and entry. Necrotic core results from apoptosis and necrosis, increased proteolytic activity and lipid accumulation. Ross, NEJM; 1999 Development of Unstable Fibrous Plaque Rupture or ulceration of fibrous cap rapidly leads to thrombosis. Occurs primarily at sites of thinning of the fibrous cap. Thinning is a result of continuing influx of and activation of macrophages which release metalloproteinases and other proteolytic enzymes. These enzymes degrade the matrix which can lead to hemorrhage and thrombus formation Ross, NEJM; 1999 Ross, NEJM; 1999 4 Plaque Rupture with Thrombus Thrombus Cholesteryl esters in lipoproteins can be selectively taken up by the receptor SR-BI (scavenger receptor, class B type I) Can bind HDL, LDL, VLDL Fibrous cap Still unclear Binds HDL, LDL, VLDL SR-BI: 1 mm Lipid core 1. 2. Illustration courtesy of Frederick J. Schoen, M.D., Ph.D. Lipids Online cluster on microvilli and in the cell surface lipid raft, not in coated pits as does the LDL receptor Mediate the transfer of lipid across the membrane, not endocytosis of entire LDL particles LDL Cellular Metabolism LDL Cellular Metabolism LDL are taken up by the LDL Receptor into clathrin-coated pits LDL dissociates from the receptor; the receptor recycles to the membrane Cholesterol and Atherosaclerosis, Grundy) Cholesterol and Atherosaclerosis, Grundy) 5 LDL Cellular Metabolism In the lysosome, lipids are deseterified; proteins are hydrolyzed LDL Cellular Metabolism Increase in free cholesterol regulates decrease cholesterol synthesis and uptake; increase cholesterol esterification Cholesterol and Atherosaclerosis, Grundy) Cholesterol and Atherosaclerosis, Grundy) Arterial inflammation and cellular import of cholesterol mark the early stage of atherosclerosis Arterial inflammation and cellular import of cholesterol mark the early stage of atherosclerosis (LDLR-independent mechanism) LDLR-independent uptake of LDL (bad cholesterol) leads to formation of foam cell (LDLR play an important role of atherosclerosis??????? No no no no這不是LDLR的錯 ) Plasma LDL→ LDL in artery high → LDLR-mediated endocytosis ↑→rapidly foam cell develop ?????? However, LDL-mediated endocytosis is not a factor for the development of atherosclerosis: Two reasons, still atherosclerosis 1. Intracellular regulation: LDLR gene activity is cholesterol-dependent; High intracellular cholesterol →insig/SCAP/SREBP pathway ↓→ LDLR gene regulation ↓→ low LDLR gene expression 2. In familial hypercholesterolemic patient: LDLR activity is lower, but still has atherosclerosis Generation of macrophage foam cells in an artery wall A site infection or damage → activated endothelial cell → cell adhesion molecular expression → monocyte adhesion → migration → differentiation to macrophage High LDL →oxidized to oxLDL → bind to scavenger receptor (macrophage) → degraded →lipid droplets cytosol → formed foam cell →ABCA1 or SR-B1→ transport HDL out via ABCA1 and/or SR-BI Scavenger receptor 6 Atherosclerosis narrows and blocks blood flow through coronay arteries A coronary artery with an atherosclerotic plaque FC: macrophage contain cholesteryl ester and lipid droplets intima Smooth muscle Reverse cholesterol transport by HDL protect against atherosclerosis Cholesterol →ABC → blood →SR-BI uptake→ liver → LCAT cholesteryl ester HDL: decrease foam cell, macrophage HDL Function Cholesteryl estertransfer protein indirectly Directly possibility of contracting atherosclerosis! LDL/HDL < 3.5 (healthy status) decrease LDL, increase HDL • • • • Removal of CE from LDL Reverse Cholesterol transport Apo A-1 prevent seeding of LDL Apo A-1 prevent oxidized LDL formation LCAT Lecithin:cholesterol acyl transferase; in plasma Fig 18-22 HDL-mediated reverse cholesterol transport 7 Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCAT sorting endosome: ligand/receptor dissociation LDL receptor Recycling Recyclingofofreceptor receptor clathrincoated pit Peripheral Cell UC diffusion Macrophage/ Foam cell ABCA1 o o o HDL UC HDL UC vesicle LDL CE HDL CE CE CE apoA-I UC = unesterified cholesterol CE = esterified cholesterol PL = phospholipid LDLr = LDL receptor VLDL or LDL apoB CE Liver LDLr Chol CERP; cholesterol efflux regulatory protein Membrane Cholesterol Bile acids Bile to gut CE in nascent HDL ACAT (stimulated by cholesterol) CE stored in Cholesterol droplets CE CE Esterase Cholesterol metabolism to bile acids or steroids Apo A1 receptor L C A T Cellular cholesterol uptake, metabolism and release. Golgi free pool of cholesterol Cholesterol release for transport to liver SR-B1 TG NPC-1 mediated transfer ACEH CE Æ cholesterol B100 Æ amino acids LCAT Nascent HDL lysosome oand clathrin o late endosome o endocytosis LCAT PL transport vesiclelysosome fuse forming late endosome A1 CII E Reverse Cholesterol Transport Apo A1 binds to receptor, activates CERP to pump out cholesterol, and LCAT to esterify cholesterol A1 E CII Mature HDL: Cleared by liver Two treatments for atherosclerosis are based on SREBPregulated cellular cholesterol metabolism 1. Bile acid-binding resins (“sequestrants”) - bind tightly to bile acid → inhibits IBAT absorption into int. epith. cell. → increased LDLR expression (Fig 18-23b) Feedback repression by bile acids on 7α-hydroxylase lost; cholesterol to bile acids greatly enhanced to maintain pool of bile acids 2. Statin (inhibitor of HMG-CoA reductase) - less cholesterol synthesized - increased LDLR expression (Fig 18-23b) IBAT : ileal bile acid transporter I-BABP : intestinal bile acid transporter NTCP : Na+-linked symporter 8 CONSEQUENCES OF BILE SALT SEQUESTERING RESINS (e.g., Cholestyramine) 1) Feedback repression by bile acids on 7α-hydroxylase; cholesterol to bile acids greatly enhanced to maintain pool of bile acids. 2) Lowered liver cholesterol up-regulates LDL receptors via SREBP induction of transcription in the liver 3) More LDL receptors increases the hepatic uptake of LDL with consequent lowering of plasma cholesterol 9