Hepatitis C Virus Attenuates Mitochondrial Lipid β-Oxidation by Downregulating Mitochondrial Trifunctional-Protein Expression

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 beta-oxidation. However, little is known about the effects of HCV on lipid beta-oxidation. A previous proteomics study revealed that HCV interacted with both the alpha- and beta-subunits of the mitochondrial trifunctional protein (MTP), an enzyme complex which catalyzes the last 3 steps of mitochondrial lipid beta-oxidation for cellular energy production. Here we show that in HCV-infected Huh7.5 cells, lipid beta-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-alpha) 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. IMPORTANCE HCV infection triggers metabolic alterations, which lead to significant disease outcomes, such as fatty liver (steatosis). This study revealed that HCV impairs mitochondrial lipid beta-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 beta-oxidation, host cells were less responsive to the ability of exogenously added IFN-alpha to suppress HCV replication. This suggests that interference with lipid beta-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.