title: Hepatitis C virus attenuates mitochondrial lipid β-oxidation by downregulating mitochondrial trifunctional-protein expression.
abstract: The course of hepatitis C virus (HCV) infection and disease progression involves alterations in lipid metabolism, leading to symptoms such as hypocholesterolemia and steatosis. Steatosis can be induced by multiple mechanisms, including increases in lipid biosynthesis and uptake, impaired lipoprotein secretion, and/or attenuation of lipid β-oxidation. However, little is known about the effects of HCV on lipid β-oxidation. A previous proteomics study revealed that HCV interacted with both the α- and β-subunits of the mitochondrial trifunctional protein (MTP), an enzyme complex which catalyzes the last 3 steps of mitochondrial lipid β-oxidation for cellular energy production. Here we show that in HCV-infected Huh7.5 cells, lipid β-oxidation was significantly attenuated. Consistently with this, MTP protein and mRNA levels were suppressed by HCV infection. A loss-of-function study showed that MTP depletion rendered cells less responsive to alpha interferon (IFN-α) treatment by impairing IFN-stimulated gene expression. These aspects of host-virus interaction explain how HCV alters host energy homeostasis and how it may also contribute to the establishment of persistent infection in the liver.
  
  
  OBJECTIVE
  HCV infection triggers metabolic alterations, which lead to significant disease outcomes, such as fatty liver (steatosis). This study revealed that HCV impairs mitochondrial lipid β-oxidation, which results in low lipid combustion. On the other hand, the HCV-induced defects in metabolic status played an important role in the control of the type I interferon system. Under the conditions of impaired lipid β-oxidation, host cells were less responsive to the ability of exogenously added IFN-α to suppress HCV replication. This suggests that interference with lipid β-oxidation may assist the virus in the establishment of a long-term, persistent infection. Further understanding of this aspect of virus-host interaction may lead to improvements in the current standard therapy.
authors: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom amako-yt@igakuken.or.jp m.harris@leeds.ac.uk.
authors: Yutaka
authors: Y
authors: Amako
authors: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors: Tsubasa
authors: T
authors: Munakata
authors: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors: Michinori
authors: M
authors: Kohara
authors: Department of Medicine, Division of Infectious Diseases, University of California, San Diego, California, USA.
authors: Aleem
authors: A
authors: Siddiqui
authors: Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom.
authors: Chris
authors: C
authors: Peers
authors: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom amako-yt@igakuken.or.jp m.harris@leeds.ac.uk.
authors: Mark
authors: M
authors: Harris
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008156:Luciferases; D063991:Mitochondrial Trifunctional Protein / Q000378:metabolism*; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016898:Interferon-alpha; D034741:RNA, Small Interfering; D008156:Luciferases; D063991:Mitochondrial Trifunctional Protein