While it is well established that branched-chain amino acid (BCAA) catabolism is impaired in obesity, detailed mechanisms how BCAA catabolism regulates glucose homeostasis is still elusive. While impaired BCAA catabolism induces glucose intolerance in skeletal muscle or brown adipose tissues, the role of BCAAs and its catabolism on liver metabolism is under-investigated.
The rate limiting step of BCAA catabolism is positively regulated by PPM1K through the dephosphrylation of branched-chain keto acid dehydrogenase (BCKDH) complex. We found that Ppm1k-deficient (KO) mice, a model of impaired BCAA catabolism, showed reduced gluconeogenesis and were protected from glucose intolerance induced by high-fat diet feeding. In primary hepatocytes, accumulation of branched chain keto acids (BCKAs), downstream metabolites of BCAAs, due to Ppm1k deficiency inhibited hepatic glucose production in a cell-autonomous manner. Interestingly, pyruvate-supported glucose production was specifically suppressed in KO mice or hepatocytes. Mechanistically, BCKAs directly inhibited liver mitochondrial pyruvate carrier (MPC) activity resulting in selective suppression of pyruvate-supported gluconeogenesis or mitochondrial respiration. Moreover, in non-hepatic mitochondria, BCKA accumulation was alleviated via the reversible reaction of branched-chain amino transferase, rendering them less susceptible to BCKA-mediated inhibition of MPC.
Together, these results suggest that BCAA catabolism regulates pyruvate and energy homeostasis in liver via BCKAs.