The interaction between HCV and nuclear receptor-mediated pathways

Abstract

Hepatitis C virus (HCV) is presently the leading indication for liver transplantation in Western countries. Treatment for HCV infection includes a combination of pegylated interferon and ribavirin, which produces highly variable response rates. This reflects the lack of information regarding the roles of host and viral components during viral pathogenesis. Vital processes regulated by the liver, including metabolism, lipid homeostasis, cellular proliferation, and the immune response, are known to be systematically dysregulated as a result of persistent HCV infection. Nuclear receptors and their ligands are recognized as indispensable regulators of liver homeostasis. Pathways mediated by the nuclear receptor superfamily have been shown to be profoundly disrupted during HCV infection, leading to an increased importance in elucidating the exact nature of this complex relationship. Expanded understanding of the role of nuclear receptors in HCV infection may therefore be an essential step in the search for a more universally effective treatment.

Figure 1. Nuclear receptor control of lipid homeostasis in the hepatocyte

PPAR-controlled fatty acid transporters CD36 and FATP import fatty acids into the hepatocyte (Motojima, 1998). These fatty acids can then be stored as triglycerides or undergo ω- or β-oxidation, principally controlled by PPARα (Reddy, 2001). Inhibition of the PPARα pathway can lead to steatosis. LXR induces lipogenic transcription factor SREBP-1c, which acts by up regulating lipogenic genes including FAS, ACC, and SCD-1 (Lima-Cabello, 2010). PPARγ also induces these genes (Gavrilova, 2003; S. Yu, 2003). PXR promotes lipogenesis through inhibition of PPARα and activation of PPARγ (Zhou, 2006). FXR inhibits lipogenesis through SHP induction, which blocks LXR. SHP also inhibits CYP7A1, the rate-limiting enzyme for the formation of bile acids (Gadaleta, 2010). ACC, acyl-coA carboxylase; AOX, acyl-coA oxidase ;CPT-1, carnitine palmitoyl transferase 1; CYP4A1, cytochrome P450 4A1; CYP7A1, cholesterol 7α-hydroxylase; FAS, fatty acid synthase; FATP, fatty acid transport protein; FXR, farnesoid X receptor; LXR, liver X receptor; PPAR, peroxisome proliferator activated receptor; PXR, pregnane X receptor; SCD-1, stearyl-coA dehydrogenase; SHP, small heterodimer partner; SREBP-1c, steroid regulatory element-binding protein.

Figure 2. Nuclear receptors and the pathogenesis of HCV

Nuclear receptor-mediated pathways influence the progression of HCV-induced chronic hepatitis. HCV infection can lead to (1) inflammation, (2) steatosis, (3) steatohepatitis, (4) fibrosis, (5) cirrhosis, and (6) HCC. Depending on the model used, conflicting results were obtained. For example, PPARα can either promote or prohibit viral replication (Lyn, 2009; Nishimura-Sakurai, 2010; Rakic, 2006; Tanaka, 2008a; Tanaka, 2008b). Some of the findings have only been found in animal or cell line models (*). Please see Table 1 for details. Depending on the stage of the disease and the cell type involved, activation of nuclear receptors can either inhibit or promote the pathogenic process. For example, activation of PPARγ and LXR favors steatosis (Moriishi, 2007; Yasui, 2010) but inhibits fibrosis (Beaven, 2010; Zhao, 2006), and activation of FXR favors viral replication (Chang, 2007) but may have anti-inflammatory and anti-fibrotic effects (Fiorucci, 2004; Fiorucci, 2005; Zhang, 2009). This complicated scheme makes treatment challenging and stage-specific treatment strategies may have to be considered. FXR, farnesoid X receptor; LXR, liver X receptor; PPAR, peroxisome proliferator activated receptor; RXR, retinoid X receptor; SHP, small heterodimer partner.