Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis

Abstract

Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease (NAFLD) is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin-sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose-limiting side effects thought to be due to activation of the peroxisome proliferator-activated receptor γ (PPARγ). We sought to determine whether a next-generation thiazolidinedione with markedly diminished ability to activate PPARγ (MSDC-0602) would retain its efficacy for treating NASH in a rodent model. We also determined whether some or all of these beneficial effects would be mediated via an inhibitory interaction with the mitochondrial pyruvate carrier 2 (MPC2), which was recently identified as a mitochondrial binding site for thiazolidinediones, including MSDC-0602. We found that MSDC-0602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans-fatty acids, fructose, and cholesterol. Moreover, mice with liver-specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC-0602 directly reduced hepatic stellate cell activation in vitro, and MSDC-0602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. Conclusion Collectively, these data demonstrate the effectiveness of MSDC-0602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacologic development.

The beneficial metabolic effects of insulin sensitizers are not attenuated by mitochondrial pyruvate carrier 2 hypomorphism

“…Interestingly, while mice fed regular HF diet or HF diet containing PIO continued to gain weight or remained static, all mice fed MSDC-0602 lost a notable amount of weight (Figure 2A, B). This loss of body weight occurred within the first week of MSDC-0602 feeding and is similar to another recent study we conducted with MSDC-0602 (McCommis et al , 2016b). Weight loss was not associated with increased locomotor activity in WT mice (Figure 2C) or an overt reduction in food intake in mice of either genotype (Figure 2D) in MSDC-0602-treated mice compared to HF-fed controls.…”

“…2A and B). This loss of body weight occurred within the first week of MSDC-0602 feeding and is similar to another recent study we conducted with MSDC-0602 (McCommis et al 2016b). Weight loss was not associated with increased locomotor activity in WT mice (Fig.…”

“…The recently described, BRET-based, MPC activity system known as RESPYR (Compan et al , 2015) can also be used to detect interactions with small molecule competitive inhibitors of MPC activity (McCommis et al , 2016b). As we have previously described, addition of UK-5099, a potent and specific MPC inhibitor, or MSDC-0602 caused a dramatic and immediate increase in RESPYR activity in HEK293 cells (Figure 7A, left panel).…”

Ketogenic Diet Prevents Heart Failure from Defective Mitochondrial Pyruvate Metabolism

“…To determine whether this decrease in cardiac MPC expression was an adaptive process in heart failure or contributes to the cardiac remodeling and dysfunction, we generated cardiacspecific Mpc2 knockouts (CS-MPC2-/-) using our established Mpc2 floxed mouse [24][25][26] and mice expressing Cre under the endogenous myosin light chain 2v promoter. CS-MPC2-/-mice had complete loss of cardiac Mpc2 gene expression (Supplemental Fig.…”

Pioglitazone for advanced fibrosis in nonalcoholic steatohepatitis: New evidence, new challenges

“…In the meantime, pharmacological research is developing compounds that keep the therapeutic effectiveness of pioglitazone, but are devoid of its unwanted effects, including selective peroxisome proliferator‐activated receptors (PPAR) γ modulators, mitochondrial target of thiazolidinediones modulators, stabilized R‐enantiomer of pioglitazone DRX‐065, and dual PPAR‐α/γ agonists, some of which yielded promising results in preclinical/phase I‐II clinical studies …”