Branched-chain amino acids alter cellular redox to induce lipid oxidation and reduce de novo lipogenesis in the liver.

Metabolic and molecular interactions between branched-chain amino acid (BCAA) and lipid metabolism are evident in insulin-resistant tissues. However, it remains unclear whether insulin resistance is a prerequisite for these relationships and whether BCAAs or their metabolic intermediates can modulate hepatic lipid oxidation and synthesis. We hypothesized that BCAAs can alter hepatic oxidative function and de novo lipogenesis, independent of them being anaplerotic substrates for the mitochondria. Mice (C57BL/6NJ) were reared on a low-fat (LF), LF diet plus 1.5X BCAAs (LB), high-fat (HF) or HF diet plus 1.5X BCAAs (HB) for 12 wk. Hepatic metabolism was profiled utilizing stable isotopes coupled to mass spectrometry and nuclear magnetic resonance, together with fed-to-fasted changes in gene and protein expression. A greater induction of lipid oxidation and ketogenesis on fasting was evident in the BCAA-supplemented, insulin-sensitive livers from LB mice, whereas their rates of hepatic de novo lipogenesis remained lower than their LF counterparts. Onset of insulin resistance in HF and HB mice livers blunted these responses. Whole body turnover of BCAAs and their ketoacids, their serum concentrations, and the ketogenic flux from BCAA catabolism, all remained similar between fasted LF and LB mice. This suggested that the impact of BCAAs on lipid metabolism can occur independent of them or their degradation products fueling anaplerosis through the liver mitochondria. Furthermore, the greater induction of lipid oxidation in the LB livers accompanied higher mitochondrial NADH/NAD ratio and higher fed-to-fasting phosphorylation of AMPKα and ACC. Taken together, our results provide evidence that BCAA supplementation, under conditions of insulin sensitivity, improved the feeding-to-fasting induction of hepatic lipid oxidation through changes in cellular redox, thus providing a favorable biochemical environment for flux through β-oxidation and lower de novo lipogenesis. Branched-chain amino acids (BCAAs) have been shown to modulate lipid metabolic networks in various tissues, especially during insulin resistance. In this study we show that the dietary supplementation of BCAAs to normal, insulin-sensitive mice resulted in higher mitochondrial NADH:NAD ratios and AMPK activation in the liver. This change in the cellular redox status provided an optimal metabolic milieu to increase fatty acid oxidation while keeping the rates of de novo lipogenesis lower in the BCAA-supplemented mice livers.