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Decreased expression of ARV1 results in cholesterol retention in the endoplasmic reticulum and abnormal bile acid metabolism.

ABSTRACT: Endoplasmic reticulum (ER) membrane cholesterol is maintained at an optimal concentration of ?5 mol % by the net impact of sterol synthesis, modification, and export. Arv1p was first identified in the yeast Saccharomyces cerevisiae as a key component of this homeostasis due to its probable role in intracellular sterol transport. Mammalian ARV1, which can fully complement the yeast lesion, encodes a ubiquitously expressed, resident ER protein. Repeated dosing of specific antisense oligonucleotides to ARV1 produced a marked reduction of ARV1 transcripts in liver, adipose, and to a lesser extent, intestine. This resulted in marked hypercholesterolemia, elevated serum bile acids, and activation of the hepatic farnesoid X receptor (FXR) regulatory pathway. Knockdown of ARV1 in murine liver and HepG2 cells was associated with accumulation of cholesterol in the ER at the expense of the plasma membrane and suppression of sterol regulatory element-binding proteins and their targets. These studies indicate a critical role of mammalian Arv1p in sterol movement from the ER and in the ensuing regulation of hepatic cholesterol and bile acid metabolism.

SUBMITTER: Tong F

PROVIDER: S-EPMC2962461 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Decreased expression of ARV1 results in cholesterol retention in the endoplasmic reticulum and abnormal bile acid metabolism.

Tong Fumin F Billheimer Jeffrey J Shechtman Caryn F CF Liu Ying Y Crooke Roseann R Graham Mark M Cohen David E DE Sturley Stephen L SL Rader Daniel J DJ

The Journal of biological chemistry 20100727 44

Endoplasmic reticulum (ER) membrane cholesterol is maintained at an optimal concentration of ∼5 mol % by the net impact of sterol synthesis, modification, and export. Arv1p was first identified in the yeast Saccharomyces cerevisiae as a key component of this homeostasis due to its probable role in intracellular sterol transport. Mammalian ARV1, which can fully complement the yeast lesion, encodes a ubiquitously expressed, resident ER protein. Repeated dosing of specific antisense oligonucleotide ...[more]

PMID: 20663892

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Project description:In order to explore effects of low levels of continuous microcystin-LR (MC-LR) (a cyanotoxin) exposure on hepatic lipid metabolism on the basis of the endoplasmic reticulum stress (ERS) pathway, we exposed adult male zebrafish to MC-LR (0, 1, 5, and 25 μg/L) for 60 days, and hepatic histopathology as well as lipid metabolic parameters were determined with mRNA levels of ERS signal molecules and downstream factors, along with genes associated with lipid metabolism in zebrafish liver. The results revealed that prolonged exposure to MC-LR remarkably altered the levels of hepatic total cholesterol and triglyceride and led to hepatic steatosis, which was also confirmed by hepatic cytoplasmic vacuolization in Hematoxylin/eosin (H&E) stain and lipid droplet accumulation in Oil Red O stain. The severity of hepatic damage and lipidation was increased in a dose-related manner. MC-LR exposure significantly upregulated transcriptional levels of ERS markers including hspa5, mapk8, and chop, indicating the occurrence of ERS in the liver of zebrafish. Concurrently, MC-LR significantly improved mRNA expression of unfolded protein response (UPR) pathway-related genes including atf6, eif2ak3, ern1, and xbp1s, suggesting that all of the three UPR branches were activated by MC-LR. MC-LR also induced significant upregulation of downstream lipid metabolism-related factors and genes including srebf1, srebf2, fatty acid synthase (fasn), acetyl-CoA carboxylase (acaca), stearoyl-CoA desaturase (scd), HMG CoA reductase (hmgcra), and HMG CoA synthase (hmgcs1), and downregulation of genes associated with lipolysis such as triglyceride hydrolase gene (atgl), hormone-sensitive enzyme gene (hsla), and carnitine palmitoyltransferase gene (cpt1aa). Our present results indicated that the cause of hepatic lipid accumulation by MC-LR was mainly by upregulating lipogenic and cholesterol genes but downregulating the expression of lipolytic genes through the induction of srebf1 and srebf2, which were involved in the activation of ERS signal pathways.

Dataset Information

Decreased expression of ARV1 results in cholesterol retention in the endoplasmic reticulum and abnormal bile acid metabolism.

Publications

Decreased expression of ARV1 results in cholesterol retention in the endoplasmic reticulum and abnormal bile acid metabolism.

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