The role of BCAA metabolism in metabolic health and disease

Abstract

It has long been postulated that dietary restriction is beneficial for ensuring longevity and extending the health span of mammals, including humans. In particular, a reduction in protein consumption has been shown to be specifically linked to the beneficial effect of dietary restriction on metabolic disorders, presumably by reducing the activity of the mechanistic target of rapamycin complex (mTORC) 1 and the reciprocal activation of AMP-activated protein kinase (AMPK) and sirtuin pathways. Although it is widely used as a dietary supplement to delay the aging process in humans, recent evidence suggests that branched-chain amino acids (BCAAs) might be a major cause of the deteriorating effect of a protein diet on aging and related disorders. In this review, we delineate the regulation of metabolic pathways for BCAAs at the tissue-specific level and summarize recent findings regarding the role of BCAAs in the control of metabolic health and disease in mammals.

Fig. 1. Schematic representation of BCAA catabolism.

The first step of BCAA catabolism is the transamination of BCAAs by BCAT1/2 to form BCKA. BCKAs can be transformed to BCAAs by the same enzyme. Subsequently, BCKAs are converted into branched-chain acyl-CoA by the BCKDH complex. Branched-chain acyl-CoA is then further oxidized to acetyl-CoA and propionyl CoA, which can then enter the TCA cycle. The activity of the BCKDH complex is regulated via the phosphorylation of the E1 enzyme by BCKDK and PP2Cm. (Box) Transcriptional regulation of BCAA catabolic enzyme-encoding genes by KLF15 (cardiac muscle) and PPARγ (adipose tissues). BCAA branched-chain amino acid, BCKA branched-chain keto acid, BCAT branched amino acid aminotransferase, BCKDH branched-chain keto acid dehydrogenase, BDKDK BCKDH kinase, PP2Cm protein phosphatase 2Cm, KLF15 Krȕppel-like factor 15, PPARγ peroxisome proliferator-activated receptor γ.