Branched-Chain Amino Acids and Pigment Epithelium-Derived Factor: Novel Therapeutic Agents for Hepatitis C Virus-Associated Insulin Resistance

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Abstract:

Recent clinical studies have shown that patients with chronic liver disease are insulin resistant. Of all etiologies of chronic liver disease including non-alcoholic fatty liver disease, the one that causes the most sever insulin resistance is hepatitis C virus (HCV) infection. Since insulin resistance promotes inflammatory and fibrogenic reactions in the liver, thus leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC) in patients with HCV infection, amelioration of insulin sensitivity may inhibit the progression of HCV-associated liver disease, and could improve the survival of these patients. HCV directly causes insulin resistance through HCV core protein-elicited proteasomal degradation of insulin receptor substrates and subsequent inactivation of intracellular insulin signaling molecules such as Akt. Furthermore, tumor necrosis factor-alpha (TNF-α) and/or triglyceride accumulation-induced nuclear factor-κB (NF-κB) activation in the liver is shown to play a role in insulin resistance in patients with HCV-related chronic liver disease as well. We, along with others, have recently found that branched-chain amino acids (BCAAs) and pigment epitheliumderived factor (PEDF) could improve the HCV-associated insulin resistance via suppression of NF-κB and preservation of insulin signaling pathway. In this review, we discuss the mechanisms for the actions of BCAAs and PEDF, and their clinical implications in insulin resistance of chronic liver disease in patients with HCV infection. We also discuss here which chemical structures could contribute to insulin-sensitization in patients with HCV infection.

Keywords: Hepatitis C virus; branched-chain amino acids; insulin receptor substrate; insulin resistance; nuclear factor-kappaB; peroxisome proliferator-activated receptor; pigment epithelium-derived factor; suppressor of cytokine signaling

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986709789909620

Affiliations: Department of Digestive Disease Information & Research, Kurume University School of Medicine. 67 Asahi-machi, Kurume 830-0011, Japan.

Publication date: December 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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