Interaction between hepatitis C virus and metabolic factors

Abstract

Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host's metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as important contributors to the development of insulin resistance in the distant peripheral tissues of HCV-infected patients and animal models. The demonstrated etiologies of HCV-induced whole-body insulin resistance include oxidative stress, lipid metabolism abnormalities, hepatic steatosis and iron overload. In addition, myriad effects of this condition have been characterized, including glucose intolerance, resistance to antiviral therapy, progression of hepatic fibrosis, development of hepatocellular carcinoma, and general decrease in quality of life. Metabolic-related conditions and disorders, such as visceral obesity and diabetes mellitus, have been shown to synergistically enhance HCV-induced metabolic disturbance, and are associated with worse prognosis. Yet, the molecular interactions between HCV-induced metabolic disturbance and host-associated metabolic factors remain largely unknown. The diet and lifestyle recommendations for chronic hepatitis C are basically the same as those for obesity, diabetes, and metabolic syndrome. Specifically, patients are suggested to restrict their dietary iron intake, abstain from alcohol and tobacco, and increase their intake of green tea and coffee (to attain the beneficial effects of caffeine and polyphenols). While successful clinical management of HCV-infected patients with metabolic disorders has also been achieved with some anti-diabetic (i.e., metformin) and anti-lipid (i.e., statins) medications, it is recommended that sulfonylurea and insulin be avoided.

Keywords: Diabetes; Hepatic steatosis; Hepatitis C virus; Insulin resistance; Iron overload; Lipid metabolism abnormality; Oxidative stress; Visceral obesity.

Figure 1

Overview of insulin signaling. Insulin binding promotes receptor autophosphorylation and subsequent tyrosine phosphorylation of insulin receptor substrates, which initiate a cascade of multifaceted metabolic actions. GLUT: Glucose transporter; IRS: Insulin receptor substrate; SOCS: Suppressor of cytokine signaling; aPKC: Atypical protein kinase; SREBP: Sterol regulatory element binding protein; mTOR: Mammalian target of rapamycin; MAPK: Mitogen-activated protein kinase; PTEN: Phosphatase and tensin homolog; GSK3: Gen synthase kinase-3; SHIP: SH2 domain-containing inositol phosphatases.

Figure 2

Molecular mechanisms of insulin resistance in hepatitis C virus-infected hepatocytes. Hepatitis C virus (HCV) can inhibit insulin signaling directly or indirectly. GLUT: Glucose transporter; IRS: Insulin receptor substrate; SOCS: Suppressor of cytokine signaling; SREBP: Sterol regulatory element binding protein; mTOR: Mammalian target of rapamycin; MAPK: Mitogen-activated protein kinase; PTEN: Phosphatase and tensin homolog; SHIP: SH2 domain-containing inositol phosphatases; GSK3: Gen synthase kinase-3; PI3K: Phosphatidyl inositol 3-kinase; TNF: Tumor necrosis factor; ER: Endoplasmic reticulum; PP2A: Protein phosphatase 2A; PA28γ: Proteasome activator 28γ.

Figure 3

Multi-organ interaction in hepatitis C virus infection. Visceral adiposity enhances hepatitis C virus (HCV)-induced whole-body insulin resistance. TNF: Tumor necrosis factor; FFA: Free fatty acid.