Pathophysiology of insulin resistance and steatosis in patients with chronic viral hepatitis

Abstract

Chronic hepatitis due to any cause leads to cirrhosis and end-stage liver disease. A growing body of literature has also shown that fatty liver due to overweight or obesity is a leading cause of cirrhosis. Due to the obesity epidemic, fatty liver is now a significant problem in clinical practice. Steatosis has an impact on the acceleration of liver damage in patients with chronic hepatitis due to other causes. An association between hepatitis C virus (HCV) infection, steatosis and the onset of insulin resistance has been reported. Insulin resistance is one of the leading factors for severe fibrosis in chronic HCV infections. Moreover, hyperinsulinemia has a deleterious effect on the management of chronic HCV. Response to therapy is increased by decreasing insulin resistance by weight loss or the use of thiazolidenediones or metformin. The underlying mechanisms of this complex interaction are not fully understood. A direct cytopathic effect of HCV has been suggested. The genomic structure of HCV (suggesting that some viral sequences are involved in the intracellular accumulation of triglycerides), lipid metabolism, the molecular links between the HCV core protein and lipid droplets (the core protein of HCV and its transcriptional regulatory function which induce a triglyceride accumulation in hepatocytes) and increased neolipogenesis and inhibited fatty acid degradation in mitochondria have been investigated.

Keywords: Adipocytokines; Fatty acids; Hepatitis B virus; Hepatitis C virus; Inducible nitric oxide synthase; Insulin resistance; Signal transduction and activator of transcription-3; Steatosis; Sterol regulatory element-binding protein-1c; Suppressors of cytokine signaling; Tumor necrosis factor-α.

Figure 1

Underlying mechanisms of the complex interaction resulting in steatosis in patients with hepatitis C virus. HCV: Hepatitis C virus.

Figure 2

Cross-talk among the insulin sensitive organs.

Figure 3

Insulin signaling pathways. PI3-K: Phosphatidyl inositol 3-kinase; AkT: A serine/threonine protein kinase.

Figure 4

Pathways to insulin resistance. PKC: Protein kinase C; IKK: Inhibitor κB kinase; TNF: Tumor necrosis factor; NF: Nuclear factor; SOCS: Suppressors of cytokine signaling; IRS: Insulin receptor substrate.

Figure 5

Insulin resistance and cell death. FFA: Free fatty acids; TGL: Tryglycerides.

Figure 6

Fate of accumulated fat within hepatocytes.