title: 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.
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Fumin
authors.initials: F
authors.lastname: Tong
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Billheimer
authors.forename: Caryn F
authors.initials: CF
authors.lastname: Shechtman
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Roseann
authors.initials: R
authors.lastname: Crooke
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Sturley
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: C467736:ARV1 protein, S cerevisiae; C553399:ARV1 protein, human; C553398:ARV1 protein, mouse; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D002784:Cholesterol