Impact of Branched Chain Amino Acid Supplementation on Hepatic Mitochondrial Metabolism in Mice with Non-alcoholic Fatty Liver Disease (P08-136-19)

Objectives Elevated circulating branched chain amino acid (BCAA) levels are correlated with the development of insulin resistance and type 2 diabetes mellitus in humans. On the other hand, BCAA supplementation has been shown to be beneficial in improving insulin resistance during chronic liver disease. Furthermore, there is recent evidence of significant crosstalk between BCAA and mitochondrial lipid metabolism. Considering the central role of dysfunctional mitochondrial lipid metabolism in diet-induced obesity and non-alcoholic fatty liver disease (NAFLD), our objective was to determine the impact of dietary BCAA supplementation on hepatic mitochondrial function, in a diet-induced mouse model of NAFLD. We hypothesized that the dietary supplementation of BCAA, together with a high fat diet, will exacerbate hepatic mitochondrial dysfunction during NAFLD. Methods C57BL/6NJ mice were fed with a control (10% kcal fat), high fat (HF; 60% kcal fat), or HF diet supplemented with BCAA (BA; 60% kcal fat; 1.5X BCAA) diet for 16 weeks. Livers from these mice were used for mitochondrial isolation, total liver and mitochondrial protein estimation, determination of amino acids and Kreb's cycle intermediates by mass spectrometry, and gene expression profiles. Results While the liver weights (g ± SEM) of HF fed mice (2.6 ± 0.36) were significantly higher than the control mice (1.5 ± 0.19), BCAA supplemented mice had significantly lower liver weights than the HF fed mice (1.8 ± 0.28). Hepatic mitochondrial protein content (µg/g liver ± SEM) was enriched in BCAA supplemented mice compared to their HF diet fed counterparts (BA, 3858 ± 476; HF, 2635 ± 394; P ˂ 0.05). Many of the organic acid intermediates of the Kreb's cycle were significantly lower in the liver of HF fed mice. Interestingly, BCAA supplementation (BA) with HF feeding restored hepatic organic acid intermediates to similar levels observed in control mice. Further, HF and BA feeding, both downregulated lipogenic gene expression (e.g., Fasn, Scd1, Acly) in the liver. Conclusions Our results suggest that BCAA supplementation enhanced hepatic mitochondrial biogenesis and oxidative metabolism in the liver of mice with NAFLD. High-fat diets which significantly suppressed the rates of de novo lipogenesis, could have provided the BCAAs, a metabolic milieu favorable for the induction of mitochondrial activity. Funding Sources National Institutes of Health (R01).