Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis

Abstract

Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.

Keywords: Atherosclerosis; Cardiovascular risk; Diabetes mellitus; Fibrosis; Hepatitis C virus; Insulin resistance; Metabolism; Steatosis.

Figure 1

Hypothetical trend of cardiovascular risk during the natural history of hepatitis C virus infection, from chronic hepatitis to decompensated cirrhosis. IR: Insulin resistance; HCV: Hepatitis C virus.

Figure 2

Mechanisms of hepatitis C virus-induced insulin resistance and steatosis and their impact on the progression of fibrosis and cardiovascular disease. In the hepatocyte, the virus interferes with insulin signalling, leads to overexpression of protein phosphatase 2A (PP2A) and suppressor of cytokine signalling-3 (SOCS-3), and down-regulates the expression of peroxisome proliferator activated receptors (PPAR) and of insulin receptor substrate (IRS): all these mechanisms lead to hepatic insulin resistance (IR). By inducing hepatic injury and activating peripheral blood mononuclear cells (PBMC), HCV increases circulating levels of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 and -18 (IL-6 and IL-18), and leads to peripheral IR and hyperinsulinemia. “Viral” and “metabolic” steatosis, together with the direct stimulus of increased insulin levels on hepatic stellate cells (HSCs), likely stimulate the progression of fibrosis. Furthermore, systemic inflammation, the procoagulative state and direct viral effects may contribute to the atherogenic process.