Hepatitis C virus infection: molecular pathways to steatosis, insulin resistance and oxidative stress

Abstract

The persistent infection with hepatitis C virus is a major cause of chronic liver disease worldwide. However, the morbidity associated with hepatitis C virus widely varies and depends on several host-related cofactors, such as age, gender, alcohol consumption, body weight, and co-infections. The objective of this review is to discuss three of these cofactors: steatosis, insulin resistance and oxidative stress. Although all may occur independently of HCV, a direct role of HCV infection in their pathogenesis has been reported. This review summarizes the current understanding and potential molecular pathways by which HCV contributes to their development.

Keywords: hepatitis C; insulin signaling; lipid accumulation; reactive oxygen species.

Figure 1.

Diagram connecting the insulin pathway and fatty acid (FA) biosynthesis. Insulin resistance may lead to steatosis by inducing the expression and/or the maturation of sterol regulatory element binding protein (SREBP)-1, leading to the increased expression of the enzyme acetyl-CoA carboxylase (ACC) and FA synthase (FAS). Insulin also inhibits FA β-oxidation by increasing malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase type 1 (CPT)-1, responsible for FA mitochondrial import. Conversely, intermediates in the triglyceride synthesis pathway may induce insulin resistance by activating inhibitors of insulin signaling, including protein kinase C (PKC)-ɛ, by phosphatidic acid (PA), mammalian target of rapamycin (mTOR) by diacyglycerol (DAG). Ceramides can inhibit Akt-mediated insulin signaling. FFA: free fatty acid, LPA: lysophosphatidic acid. Numbers refer to the bibliographic references.

Figure 2.

Schematic representation of some of the effects brought about by HCV on insulin signaling in hepatocytes. HCV has been shown to interfere with the insulin pathway at multiple non-exclusive levels: The HCV core can activate inhibitors of insulin signaling including the mammalian target of rapamycin (mTOR) and the suppressor of cytokine signaling (SOCS)-3 and c-Jun N-terminal kinase (JNK), either directly or indirectly via an increased secretion of tumor necrosis factor (TNF)-α, which suppress IRS-1 activation of phosphatidylinositol 3 (PI3)-kinase. Among the indirect mechanisms, an increased endoplasmic reticulum (ER) stress can lead to the activation of the protein phosphatase 2A (PP2A), an inhibitor of Akt. Activation of PP2A may also dephosphorylate the AMP-activated kinase (AMPK), a key regulator of gluconeogenesis. PKD1/2: protein kinase D1/2; p85/p110: subunits p85 and p110 of PI3-kinase. Numbers refer to the bibliographic references.

Figure 3.

Schematic representation of the effects of HCV on oxidative stress. HCV can induce reactive oxygen species (ROS) via multiple mechanisms: The particular localization of the core protein within the outer membrane of mitochondria may induce increased oxidation of mitochondria glutathione (GSH) and facilitate the uptake of Ca²⁺ into the mitochondria by sensitizing mitochondria to mitochondrial permeability transition. There is an increase in ROS production by mitochondrial electron transport complex I (circles with roman letters, the sites of ROS production in the mitochondrial electron transport chain have been localized in Complex I and Complex III) and a redistribution of cytochrome c (cyt c) from the mitochondrial to cytosolic fractions. The HCV nonstructural proteins including NS5A are associated with the membrane of the endoplasmic reticulum (ER), which activates the release of Ca²⁺ from ER, thereby inducing oxidative stress. NS3 has been shown to trigger ROS production via activation of NADPH oxidase 2 (Nox2). Numbers refer to the bibliographic references.

Figure 4.

Schematic representation of the effects of HCV on steatosis development. HCV may interfere with lipid metabolism via at least three distinct, non-mutually exclusive mechanisms: (i) Impaired secretion. HCV may interfere with the very-low density lipoprotein (VLDL) assembly and/or secretion. Both apolipoprotein B (ApoB) secretion and microsomal triglyceride transfer protein (MTP) activity are impaired by HCV core protein expression. (ii) Increased de novo synthesis of free fatty acids (FFA). HCV has been reported to upregulate sterol regulatory element binding protein (SREBP)-1c signaling pathway, leading to the up-regulation of enzymes involved in lipogenesis such as FA synthase (FAS). (iii) Impaired FA degradation. The HCV core protein reduces the expression of peroxisome proliferators-activated receptor (PPAR)-α, a nuclear receptor regulating several genes responsible for FA degradation, as well as that of mitochondrial carnitine palmitoyltransferase type 1 (CPT)-1, the rate-limiting enzyme of mitochondrial β-oxidation. ACC: acetyl-CoA carboxylase; SCD: stearoyl coenzymeA desaturase. Numbers refer to the bibliographic references.