title: Hepatitis C Virus-Induced Degradation of Cell Death-Inducing DFFA-Like Effector B Leads to Hepatic Lipid Dysregulation.
abstract: Individuals chronically infected with hepatitis C virus (HCV) commonly exhibit hepatic intracellular lipid accumulation, termed steatosis. HCV infection perturbs host lipid metabolism through both cellular and virus-induced mechanisms, with the viral core protein playing an important role in steatosis development. We have recently identified a liver protein, the cell death-inducing DFFA-like effector B (CIDEB), as an HCV entry host dependence factor that is downregulated by HCV infection in a cell culture model. In this study, we investigated the biological significance and molecular mechanism of this downregulation. HCV infection in a mouse model downregulated CIDEB in the liver tissue, and knockout of the CIDEB gene in a hepatoma cell line results in multiple aspects of lipid dysregulation that can contribute to hepatic steatosis, including reduced triglyceride secretion, lower lipidation of very-low-density lipoproteins, and increased lipid droplet (LD) stability. The potential link between CIDEB downregulation and steatosis is further supported by the requirement of the HCV core and its LD localization for CIDEB downregulation, which utilize a proteolytic cleavage event that is independent of the cellular proteasomal degradation of CIDEB.
  
  
  OBJECTIVE
  Our data demonstrate that HCV infection of human hepatocytesin vitroandin vivoresults in CIDEB downregulation via a proteolytic cleavage event. Reduction of CIDEB protein levels by HCV or gene editing, in turn, leads to multiple aspects of lipid dysregulation, including LD stabilization. Consequently, CIDEB downregulation may contribute to HCV-induced hepatic steatosis.
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Emily M
authors: EM
authors: Lee
authors: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors: Ali
authors: A
authors: Alsagheir
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Xianfang
authors: X
authors: Wu
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Christy
authors: C
authors: Hammack
authors: MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
authors: John
authors: J
authors: McLauchlan
authors: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Noriyuki
authors: N
authors: Watanabe
authors: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Takaji
authors: T
authors: Wakita
authors: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors: Norman M
authors: NM
authors: Kneteman
authors: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors: Donna N
authors: DN
authors: Douglas
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA tang@bio.fsu.edu.
authors: Hengli
authors: H
authors: Tang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D005234:Fatty Liver / Q000378:metabolism* / Q000821:virology; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids; D008099:Liver / Q000378:metabolism*; D051379:Mice; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C112511:CIDEB protein, human; D008055:Lipids; D025801:Ubiquitin