Association of lipid droplet and hepatitis C virus proteins: insights for virus replication

Abstract

Hepatitis C virus (HCV) infection represents a major worldwide disease burden, with an estimated prevalence of >185 million people ( 1 ). Among the various comorbidities associated with chronic HCV infection, hepatic steatosis is a frequent complication, and its presence is a key prognostic indicator associated with progression to hepatic fi brosis and with the development of hepatocellular carcinoma ( 2 ). Several mechanisms have been proposed to account for the development of steatosis and fatty liver in the setting of HCV infection ( 3 ). HCV infection enhances lipogenesis, reduces secretion of VLDL, attenuates ␤ -oxidation of lipids, and increases virus growth and replication through complex pathways that intersect via modulating host cell lipid metabolism ( 4 ). In addition, recent studies have implicated lipid droplet formation and turnover in the life cycle of HCV. Specifi cally, studies have identifi ed a role for the triglyceride-synthesizing enzyme diacylglycerol acyltransferase 1 (DGAT1) in both the formation of lipid droplets within the bilayer of the endoplasmic reticulum (ER) and also in the formation of infectious virions ( 5 ). Those studies demonstrated that DGAT1 (but not DGAT2) physically interacts with components of the nucleocapsid core and in turn recruits the viral replication complex to the newly generated lipid droplets ( 5 ). In addition, more-recent studies have demonstrated that this physical interaction between DGAT1 and HCV core components then interferes with triglyceride lipolysis and lipid droplet turnover, an effect that further enhances hepatic steatosis ( 6 ). These fi ndings collectively suggest that HCV infection impacts hepatic lipid metabolism over a broad range of pathways, including coopting elements of lipid droplet formation and turnover as well as modulating lipogenesis, FA oxidation, and VLDL secretion. However, despite the obvious public health impact and importance of HCV infection and its role in modulating hepatic lipid metabolism, there is still much to learn about the molecular and biochemical mechanisms by which the structural and nonstructural protein components of the HCV function within these pathways. This relative dearth of information is at least partially explained by the lack of preclinical experimental models of replicating HCV. Accordingly, most of the available information still derives from studies using transfected cell lines that support HCV genome replication, either as subgenomic or full-length constructs.With this background, the article from Tanaka et al. ( 7 ) in this issue of The Journal of Lipid Research provides new insights into the role of HCV NS4B (a nonstructural protein of the virus, known to be an integral ER membrane protein) and its association with lipid droplets. The authors demonstrated this association using state-of-the-art confocal imaging and biochemical fractionation of cell lines supporting HCV replication. Although the association of HCV with lipid droplets is well known (Moradpour et al., 1996; Miyanari et al., 2007, c...