Obesity and related metabolic abnormalities, including
insulin resistance, are risk factors for
hepatocellular carcinoma in non-
alcoholic steatohepatitis as well as in chronic viral
hepatitis.
Branched-chain amino acids (BCAA), which improve
insulin resistance, inhibited
obesity-related colon
carcinogenesis in a rodent model, and also reduced the incidence of
hepatocellular carcinoma in obese patients with
liver cirrhosis. In the present study, we determined the effects of BCAA on the development of
diethylnitrosamine (DEN)-induced liver
tumorigenesis in obese C57BL/KsJ-db/db (db/db) mice with
diabetes mellitus. Male db/db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or
casein, which served as a
nitrogen content-matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of
insulin-like growth factor (IGF)-1,
IGF-2, and
IGF-1 receptor in the liver when compared to the
casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular
neoplasms and the proliferation of hepatocytes in comparison to the basal diet or
casein-fed groups. Supplementation with BCAA improved
liver steatosis and
fibrosis and inhibited the expression of alpha-smooth muscle actin in the DEN-treated db/db mice. The serum levels of
glucose and
leptin decreased by dietary BCAA, whereas the value of the quantitative
insulin sensitivity check index increased by this agent, indicating the improvement of
insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves
insulin resistance and prevents the development of liver
tumorigenesis in obese and diabetic mice.