Studies on animal models have demonstrated that feeding a low-
arginine diet inhibits
triacylglycerol (TAG) secretion from the liver, resulting in marked
fatty liver development in rats. Here, we first showed that culturing hepatocytes in the medium mimicking the serum
amino acid profile of low-
arginine diet-fed rats induced TAG accumulation in the cells, indicating that the specific
amino acid profile caused TAG accumulation in hepatocytes. Dietary
adenine supplementation completely recovered hepatic TAG secretion and abolished hepatic TAG accumulation in rats. A comprehensive non-linear analysis revealed that inhibition of hepatic TAG accumulation by dietary
adenine supplementation could be predicted using only serum
amino acid concentration data. Comparison of serum
amino acid concentrations indicated that
histidine,
methionine, and
branched-chain amino acid (BCAA) concentrations were altered by
adenine supplementation. Furthermore, when the serum
amino acid profiles of low-
arginine diet-fed rats were altered by modifying
methionine or BCAA concentrations in their diets, their hepatic TAG accumulation was abolished. Altogether, these results suggest that an increase in
methionine and BCAA levels in the serum in response to dietary
arginine deficiency is a key causative factor for hepatic TAG accumulation, and dietary
adenine supplementation could disrupt this phenomenon by altering serum
amino acid profiles.