Regulating Hepatic Cellular Cholesterol

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Angel Dickerson
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Under circumstances of cholesterol deficiency, Sterol Regulatory Element Binding Proteins (SREBPs) via binding to DNA nuclear response elements set off genomic

Regulating Hepatic ellular SREBP Lipogenic Enzymes mrna Endoplasmic Reticulum HMG-oA Reductase Negative Feedback Geranyl-PP Acetyl-oA HMG-oA Reduction Mevalonate

1 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 HMGoA reductase. Regulating Hepatic ellular SREBP Lipogenic Enzymes mrna Endoplasmic Reticulum HMG-oA Reductase Negative Feedback Geranyl-PP Acetyl-oA HMG-oA Reduction Mevalonate Squalene Farnesyl-PP Hepatic Sinusoid 19 steps including multiple intermediaries including lathosterol Depleted Pool Synthesis Geranlygeranyl-PP Isoprenoids Sterol Regulatory Element Binding Protein 2 (SREBP-2) regulates Synthesis Bile Duct

2 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 1 Like 1 protein at the hepatobiliary interface is another source of cholesterol for the hepatocyte. Regulating Hepatic ellular Endoplasmic Reticulum mrna Nucleus DNA LDL receptor synthesis & translocation to cell membrane Decreased cholesterol pool holesteryl ester Sterol Regulatory Element Binding Proteins sense the low sterols Niemann Pick 1 Like 1 Protein Biliary free cholesterol Bile Duct Hepatic Sinusoid LDL receptor endocytosis of LDL particles carrying cholesteryl ester facilitates cholesterol movement from bile back to hepatocytes

Sterol cellular toxicity (crystallization) is prevented primarily by the liver X receptors () and the

FXRs cross talk with the via the short heterodimer protein (SHP).

transporters namely ABA1, ABG5 and ABG8 and ABB11.

driven exportation of cholesterol (ABA1,ABG5,G8), non cholesterol sterols (ABG5,G8) or bile acids

The also by inducing cholesterol 7 alpha hydroxylase induce synthesis of bile acids with are excreted

Suppression of HMGoA reductase would also help correct sterol toxicity as would suppression of the

Regulating Hepatic ellular Liver X Receptors Prevent Sterol Toxicity Heterodimerization with Retinoid

3 Sterol cellular toxicity (crystallization) is prevented primarily by the liver X receptors () and the Farnesol or Farnesoid X receptors (FXR). The latter regulate bile acids. FXRs cross talk with the via the short heterodimer protein (SHP). Under circumstances of hepatic sterol excess, s induce the synthesis of several ATP binding cassette transporters namely ABA1, ABG5 and ABG8 and ABB11. All of these after synthesis translocate to various membrane areas and are involved with energy driven exportation of cholesterol (ABA1,ABG5,G8), non cholesterol sterols (ABG5,G8) or bile acids (ABB11). The also by inducing cholesterol 7 alpha hydroxylase induce synthesis of bile acids with are excreted into the bile via the ABB11 transporter. Suppression of HMGoA reductase would also help correct sterol toxicity as would suppression of the hepatobiliary and intestinal upregulaltion of the protein. Regulating Hepatic ellular Liver X Receptors Prevent Sterol Toxicity Heterodimerization with Retinoid X Receptor RXR mrna holate Endoplasmic Reticulum 7α hydroxylase Acetyl-oA HMG-oA Reductase Mevalonate Lathosterol Liver X Receptors () regulate Plasma cellular sterol homeostasis and are upregulated as sterol levels rise Prebeta HDL Niemann Pick 1 Like 1 Protein Bile ductule ABB11 ABG5/8 ABA1 Hepatic influences regulation of proteins involved with sterol homeostasis including sterol efflux transporters, and BA enzymes

This slide demonstrates the actions of and FXR agonism.

FXR, or the bile acid toxicity nuclear transcription factor, suppress conversion of cholesterol to bile acids whereas induces it.

transporter) and the multidrug resistance proteins 2/3 (MDR2/3) to secrete phospholipids into bile.

4 This slide demonstrates the actions of and FXR agonism. Like so many of the lipid nuclear transcription factors, the 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 induces it. upregulates the ABG5, G8) transporter to efflux cholesterol and noncholesterol sterols into the bile whereas the FXR indices the ABB11 (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 (especially isoform alpha) induces it. FXR and Regulation of, Triglycerides and Bile Acids ABG5/G8 Heterodimerization with RXR Acetyl oa FXR SREPB-1c Bile Duct FXR FA, TG MDRP2/3 FXR Bile Acids ABB11 Bile salt export pump (BSEP) Kalaany & Mangelsdorf. Ann Rev Physiol 2006;68:159 Phospholipids VLDL (TG levels)

Nuclear transcription factors also control enterocyte handling (absorption and excretion) of sterols.

Once in the enterocyte induces acylcholesterol acyltransferase (AAT) to change cholesterol into cholesteryl ester (E). AAT cannot esterify noncholesterol sterols.

The also upregulates enterocyte ABA1 which exports unesterified (free) cholesterol into unlipidated apoa-i or prebeta HDL species. Upwards of 20-30% of total HDL- is acquired intestinally.

5 Nuclear transcription factors also control enterocyte handling (absorption and excretion) of sterols. The Niemann Pick 1 Like 1 protein () attaches to and delipidates sterols from the biliary micelles. Once in the enterocyte induces acylcholesterol acyltransferase (AAT) to change cholesterol into cholesteryl ester (E). AAT cannot esterify noncholesterol sterols. E joins with enterocyte formed TG and apolipoprotein B48 in the genesis of chylomicrons which are secreted into lacteals. The also upregulates enterocyte ABA1 which exports unesterified (free) cholesterol into unlipidated apoa-i or prebeta HDL species. Upwards of 20-30% of total HDL- is acquired intestinally. Excess cholesterol and all noncholesterol sterols can be excreted back to the intestinal lumen via the AB5 and ABG8 half transporters (sometimes called sterolin). Under conditions of sterol excess the protein can be down regulated. Enterocytes and Sterols Sterol excess in enterocytes cause to up-regulate AAT, ABA1 and ABG5, G8 and down-regulate the sterol permease Enterocyte Niemann Pick 1 like 1 protein () facilitates sterol entry from biliary micelles Mature alpha HDL Prebeta HDL 2 ABG5/G8 Absorbed Free Gut Lumen 3 RXR Plasma ABA1 Net effect of enterocyte agonism is decreased sterol absorption and increased sterol efflux 4 TG AAT 1 holesteryl ester Lacteal hylomicrons Micelles

Enterocyte sterol deficiency will cause a suppression of the :

There will also be down regulation of the protein.

cholesterol content and sterol excretion into the gut lumen.

All of these changes can be seen in persons using statins, which

why statins increase noncholesterol sterol levels.

cause to down-regulate AAT, ABA1 and ABG5, G8 and up-regulate the

6 Enterocyte sterol deficiency will cause a suppression of the : AAT, ABA1, ABG5,G8 expression is down regulated. There will also be down regulation of the 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 DEFIIENY in enterocytes cause to down-regulate AAT, ABA1 and ABG5, G8 and up-regulate the sterol permease Enterocyte Plasma Prebeta HDL ABG5/G8 Gut Lumen Decreased Pool RXR ABA1 TG AAT holesteryl ester Lacteal hylomicrons Micelles

7 In summary sterols enter via the protein and cholesterol but not noncholesterol sterols are esterified by AAT2. The E, and any noncholesterol sterols not excreted by ABG5,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 ABA1 and acquire additional unesterified cholesterol. All of the proteins in blue in the slide are under the influence of. Sterol Absorption and Enterocyte Sterols of dietary or biliary origin E () Lacteal apob48 TG hylomicron AAT2 LPL Noncholesterol sterols (N) N ABA1 N HDL ABG5 ABG8 Gut Adapted from irc Res 2004;95: AB = ATP Binding assette Transporters AAT2 = acyl cholesteryl acyl transferase = free or unesterified cholesterol E = cholesteryl ester N = Non cholesterol sterols = Niemann-Pick 1 like 1 protein hylomicron Remnant apoa-i Plasma Target Genes

Unit IV Problem 3 Biochemistry: Cholesterol Metabolism and Lipoproteins

Unit IV Problem 3 Biochemistry: Cholesterol Metabolism and Lipoproteins - Cholesterol: It is a sterol which is found in all eukaryotic cells and contains an oxygen (as a hydroxyl group OH) on Carbon number