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Nuclear Transcription Factors That Regulate Sterols Thomas Dayspring MD, FACP

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Nuclear Transcription Factors That Regulate Sterols Thomas Dayspring MD, FACP Nuclear Transcription Factors that Regulate Sterols Thomas Dayspring MD, FACP Under circumstances of cholesterol deficiency, Sterol Regulatory Element Binding Proteins (SREBPs) via binding to DNA nuclear response elements set off genomic production of proteins and enzymes that induce cholesterol synthesis, such as HMGCoA reductase. Regulating Hepatic Cellular Cholesterol Hepatic Lipogenic Enzymes Sinusoid Acetyl-CoA Hepatocyte HMG-CoA HMG-CoA Reduction mRNA Reductase Endoplasmic Mevalonate SREBP Reticulum Geranyl-PP Farnesyl-PP Negative Feedback Squalene 19 steps including multiple intermediaries Geranlygeranyl-PP including lathosterol DepletedCholesterol Cholesterol Pool Isoprenoids Synthesis Sterol Regulatory Element Binding Protein 2 (SREBP-2) regulates Cholesterol Synthesis Bile Duct Nuclear Transcription Factors that Regulate Sterols Thomas Dayspring MD, FACP SREBs also induce synthesis of LDL receptors which translocate to the surface of the cell and endocytose lipoproteins with apoE or apoB on their surface. These lipoproteins of course deliver sterols in this “indirect reverse cholesterol transport” process. Upregulation of the Niemann Pick C1 Like 1 protein NPC1L1 at the hepatobiliary interface is another source of cholesterol for the hepatocyte. Regulating Hepatic Cellular Cholesterol Hepatocyte LDL receptor synthesis & translocation to cell membrane Endoplasmic Reticulum Decreased cholesterol pool Cholesteryl mRNA ester Nucleus DNA Sterol Regulatory Element Binding Proteins Hepatic Sinusoid sense the low sterols LDL receptor endocytosis of LDL NPC1L1 Niemann Pick C1 Bile particles carrying cholesteryl ester Like 1 Protein Duct Biliary free NPC1L1 facilitates cholesterol movement cholesterol from bile back to hepatocytes Nuclear Transcription Factors that Regulate Sterols Thomas Dayspring MD, FACP Sterol cellular toxicity (crystallization) is prevented primarily by the liver X receptors (LXR) and the Farnesol or Farnesoid X receptors (FXR). The latter regulate bile acids. FXRs cross talk with the LXR via the short heterodimer protein (SHP). Under circumstances of hepatic sterol excess, LXRs induce the synthesis of several ATP binding cassette transporters namely ABCA1, ABCG5 and ABCG8 and ABCB11. All of these after synthesis translocate to various membrane areas and are involved with energy driven exportation of cholesterol (ABCA1,ABCG5,G8), non cholesterol sterols (ABCG5,G8) or bile acids (ABCB11). The LXR also by inducing cholesterol 7 alpha hydroxylase induce synthesis of bile acids with are excreted into the bile via the ABCB11 transporter. Suppression of HMGCoA reductase would also help correct sterol toxicity as would suppression of the hepatobiliary and intestinal upregulaltion of the NPC1L1 protein. Regulating Hepatic Cellular Cholesterol Liver X Receptors Prevent Sterol Toxicity Liver X Receptors (LXR) Heterodimerization with Retinoid X Receptor regulate Plasmacellular sterol homeostasis and are RXR Endoplasmic upregulated as sterol Reticulum Acetyl-CoA HMG-CoA Reductase levels rise Mevalonate LXR Lathosterol mRNA Cholesterol 7α Cholesterol Prebeta HDL Cholate hydroxylase Hepatic LXR Niemann Pick C1 Like 1 Protein ABCA1 influences regulation of proteins involved with sterol NPC1L1 homeostasis including sterol ABCB11 ABCG5/8 efflux transporters, NPC1L1 and BA Bile ductule enzymes Nuclear Transcription Factors that Regulate Sterols Thomas Dayspring MD, FACP This slide demonstrates the actions of LXR and FXR agonism. Like so many of the lipid nuclear transcription factors, the LXR and FXR heterodimerize with the RXR to facilitate attachment to the proper DNA response elements. FXR, or the bile acid toxicity nuclear transcription factor, suppress conversion of cholesterol to bile acids whereas LXR induces it. LXR upregulates the ABCG5, G8) transporter to efflux cholesterol and noncholesterol sterols into the bile whereas the FXR indices the ABCB11 (bile acid transporter) and the multidrug resistance proteins 2/3 (MDR2/3) to secrete phospholipids into bile. FXR inhibits SREBP 1c and TG synthesis whereas LXR (especially LXR isoform alpha) induces it. FXR and LXR Regulation of Cholesterol, Triglycerides and Bile Acids Hepatocyte Hepatocyte Heterodimerization with RXR ABCG5/G8 Acetyl CoA Cholesterol FXR SREPB-1c LXR LXR Bile Duct FA, TG FXR MDRP2/3 FXR Bile Acids ABCB11 VLDL Bile salt export Phospholipids (TG levels) pump (BSEP) Kalaany & Mangelsdorf. Ann Rev Physiol 2006;68:159 Nuclear Transcription Factors that Regulate Sterols Thomas Dayspring MD, FACP Nuclear transcription factors also control enterocyte handling (absorption and excretion) of sterols. The Niemann Pick C1 Like 1 protein (NPC1L1) attaches to and delipidates sterols from the biliary micelles. Once in the enterocyte LXR induces acylcholesterol acyltransferase (ACAT) to change cholesterol into cholesteryl ester (CE). ACAT cannot esterify noncholesterol sterols. CE joins with enterocyte formed TG and apolipoprotein B48 in the genesis of chylomicrons which are secreted into lacteals. The LXR also upregulates enterocyte ABCA1 which exports unesterified (free) cholesterol into unlipidated apoA-I or prebeta HDL species. Upwards of 20-30% of total HDL-C is acquired intestinally. Excess cholesterol and all noncholesterol sterols can be excreted back to the intestinal lumen via the ABC5 and ABCG8 half transporters (sometimes called sterolin). Under conditions of sterol excess the NPC1L1 protein can be down regulated. Enterocytes and Sterols Sterol excess in enterocytes cause LXR to up-regulate ACAT, ABCA1 and ABCG5, G8 and down-regulate the sterol permease NPC1L1 Enterocyte Gut Niemann Pick C1 like 1 protein (NPC1L1) ABCG5/G8 facilitates sterol entry from biliary micelles Lumen Absorbed Free Cholesterol 3 2 Mature Prebeta HDL alpha HDL RXR LXR Plasma ABCA1 4 NPC1L1 Net effect of enterocyte LXR agonism is decreased sterol absorption and increased sterol efflux TG ACAT 1 Cholesteryl Lacteal ester Micelles Chylomicrons Nuclear Transcription Factors that Regulate Sterols Thomas Dayspring MD, FACP Enterocyte sterol deficiency will cause a suppression of the LXR: ACAT, ABCA1, ABCG5,G8 expression is down regulated. There will also be down regulation of the NPC1L1 protein. This will decrease chylomicron cholesterol content, HDL cholesterol content and sterol excretion into the gut lumen. It will also cause the retention of noncholesterol sterols. All of these changes can be seen in persons using statins, which likely explains what used to be termed statin tachyphylaxis and why statins increase noncholesterol sterol levels. Enterocytes and Sterol Acquisition Sterol DEFICIENCY in enterocytes cause LXR to down-regulate ACAT, ABCA1 and ABCG5, G8 and up-regulate the sterol permease NPC1L1 Enterocyte Gut Plasma ABCG5/G8 Lumen Prebeta HDL Decreased Cholesterol Pool RXR LXR ABCA1 NPC1L1 TG ACAT Cholesteryl Lacteal ester Micelles Chylomicrons Nuclear Transcription Factors that Regulate Sterols Thomas Dayspring MD, FACP In summary sterols enter via the NPC1L1 protein and cholesterol but not noncholesterol sterols are esterified by ACAT2. The CE, and any noncholesterol sterols not excreted by ABCG5,G8 joins with intestinally resynthesized TG, apoB48 into chylomicron formation. After secretion into lacteals, where the chylomicrons acquire several other surface apolipoproteins from lymphatic HDLs, they enter the venous and ultimately the arterial circulation where they are exposed to lipoprotein lipase (LPL) at muscular and adipocyte vascular endothelium. Lipolysis of chylomicrons releases phospholipids, fatty acids and surface apoA-I. Unlipidated apoA-I and prebeta HDLs can attach to enterocyte ABCA1 and acquire additional unesterified cholesterol. All of the proteins in blue in the slide are under the influence of LXR. Sterol Absorption and LXR Sterols of Enterocyte Lacteal dietary or biliary origin apoB48 CE TG Chylomicron Cholesterol (C) NPC1L1 ACAT2 LPL C Noncholesterol sterols (NC) C NC ABCA1 Chylomicron NC HDL Remnant ABCG5 ABCG8 C C apoA-I ABC = ATP Binding Cassette Transporters Gut ACAT2 = acyl cholesteryl acyl transferase Plasma C = free or unesterified cholesterol CE = cholesteryl ester Adapted from Circ Res 2004;95:660-670 NC = Non cholesterol sterols LXR Target Genes NPC1L1 = Niemann-Pick C1 like 1 protein .
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