{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:39:59Z","timestamp":1790728799340,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2017,3,30]],"date-time":"2017-03-30T00:00:00Z","timestamp":1490832000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1"},{"start":{"date-parts":[[2017,3,30]],"date-time":"2017-03-30T00:00:00Z","timestamp":1490832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:p>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\u2010sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose\u2010limiting side effects thought to be due to activation of the peroxisome proliferator\u2013activated receptor \u03b3. We sought to determine whether a next\u2010generation thiazolidinedione with markedly diminished ability to activate peroxisome proliferator\u2013activated receptor \u03b3 (MSDC\u20100602) 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\u20100602. We found that MSDC\u20100602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans\u2010fatty acids, fructose, and cholesterol. Moreover, mice with liver\u2010specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC\u20100602 directly reduced hepatic stellate cell activation <jats:italic toggle=\"yes\">in vitro<\/jats:italic>, and MSDC\u20100602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Collectively, these data demonstrate the effectiveness of MSDC\u20100602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacologic development. (H<jats:sc>epatology<\/jats:sc> 2017;65:1543\u20101556).<\/jats:p>","DOI":"10.1002\/hep.29025","type":"journal-article","created":{"date-parts":[[2016,12,28]],"date-time":"2016-12-28T00:09:18Z","timestamp":1482883758000},"page":"1543-1556","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":137,"title":["Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis"],"prefix":"10.1097","volume":"65","author":[{"given":"Kyle S.","family":"McCommis","sequence":"first","affiliation":[{"name":"Departments of Medicine,Washington University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley T.","family":"Hodges","sequence":"additional","affiliation":[{"name":"Departments of Medicine,Washington University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth 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