Branched-chain amino acids and pigment epithelium-derived factor: novel therapeutic agents for hepatitis c virus-associated insulin resistance.
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-alpha) and/or triglyceride accumulation-induced nuclear factor-kappaB (NF-kappaB) 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 epithelium-derived factor (PEDF) could improve the HCV-associated insulin resistance via suppression of NF-kappaB 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.
Kawaguchi
T
T
Department of Digestive Disease Information & Research, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. takumi@med.kurume-u.ac.jp
Yamagishi
S
S
Sata
M
M
D000597:Amino Acids, Branched-Chain / Q000494:pharmacology* / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy; D005136:Eye Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D006526:Hepatitis C / Q000150:complications*; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology* / Q000627:therapeutic use; D000099174:Pigment Epithelium-Derived Factor
D000597:Amino Acids, Branched-Chain; D005136:Eye Proteins; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D016328:NF-kappa B; D009414:Nerve Growth Factors; D047492:Peroxisome Proliferator-Activated Receptors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor