Colca, J. R. | Search bioRxiv

bioRxiv2022

Mitochondrial Pyruvate Carrier Inhibition Initiates Metabolic Crosstalk to Stimulate Branched Chain Amino Acid Catabolism

ObjectiveThe mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. MethodsCirculating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg MSDC-0602K (n = 101). Human hepatoma cell lines were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA catabolism in the liver of obese mice. ResultsIn patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades. Finally, BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo. ConclusionsThese data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the AMPK/mTOR axis.

physiology↗

bioRxiv2020

MSDC-0602K, A Novel Insulin-Sensitizer Improves Insulinemia and Fatty Liver Disease Alone and in Addition to Liraglutide in Mice

Aims/hypothesisInsulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanisms of action. Additionally, while thiazolidinedione (TZD) insulin sensitizers are associated with the side-effect of weight gain, glucagon-like peptide-1 receptor agonists (GLP-1RAs) can induce weight loss. We hypothesized that combination therapy with a novel TZD insulin sensitizer and the GLP-1RA Liraglutide would more significantly improve mouse models of diabetes and nonalcoholic steatohepatitis (NASH) compared to individual therapy. Methodsdb/db mice were treated with the novel TZD MSDC-0602K by oral gavage, Liraglutide (Lira) by s.c. injection, combination 0602K+Lira, or both vehicle solutions. Vehicle-treated db/+ mice were included as non-obese controls. To assess treatment effects on nonalcoholic fatty liver disease, MS-NASH mice were similarly treated with vehicle, either drug individually, or in combination. Lastly, islets were isolated from C57BL/6J mice to assess glucose-stimulated insulin secretion (GSIS). Results0602K-treated db/db mice displayed slight weight gain but completely corrected glycemia and markedly improved glucose tolerance. Lira slightly reduced body weights and modestly improved glycemia. 0602K+Lira combination still induced slight weight gain but completely corrected glycemia and improved glucose tolerance beyond lean db/+ levels. As expected, 0602K resulted in reduced plasma insulin, whereas Lira further increased the hyperinsulinemia of db/db mice. Surprisingly, 0602K+Lira treatment reduced plasma insulin and C-peptide to the same extent as mice treated with 0602K alone. 0602K did not directly reduce GSIS in isolated islets, thus the reduced insulinemia with 0602K is likely compensatory due to improved insulin action. In the MS-NASH mouse model, both 0602K or Lira alone improved plasma ALT and AST, and liver histology, but more significant improvements were observed with 0602K+Lira combination therapy. 0602K or 0602K+Lira also increased pancreatic insulin content in both db/db and MS-NASH mice. ConclusionsMSDC-0602K corrected glycemia and reduced insulinemia when given alone, or in combination with Lira. However, 0602K+Lira combination more significantly improved glucose tolerance in db/db mice, and more significantly improved liver histology in MS-NASH mice.

pharmacology and toxicology↗