title: 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 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. We sought to determine whether a next-generation thiazolidinedione with markedly diminished ability to activate peroxisome proliferator-activated receptor γ (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 through 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.
  
  
  
  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. (Hepatology 2017;65:1543-1556).
authors.affiliation: Departments of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Kyle S
authors.initials: KS
authors.lastname: McCommis
authors.affiliation: Departments of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Wesley T
authors.initials: WT
authors.lastname: Hodges
authors.affiliation: Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.affiliation: Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Ilke
authors.initials: I
authors.lastname: Nalbantoglu
authors.affiliation: Metabolic Solutions Development Company, Kalamazoo, MI.
authors.forename: William G
authors.initials: WG
authors.lastname: McDonald
authors.affiliation: Departments of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Christopher
authors.identifier: 0000-0002-2870-3352
authors.initials: C
authors.lastname: Holley
authors.affiliation: Departments of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Hideji
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Departments of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
authors.affiliation: Metabolic Solutions Development Company, Kalamazoo, MI.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Colca
authors.affiliation: Departments of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D000098:Acetophenones / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D027321:Anion Transport Proteins / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D055354:Exosomes / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D011897:Random Allocation; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000098:Acetophenones; D027321:Anion Transport Proteins; C000595574:MPC2 pyruvate carrier protein, mouse; C000619119:MSDC-0602; D033681:Mitochondrial Membrane Transport Proteins; D045162:Thiazolidinediones