Dataset Information

Treating Hepatic Steatosis and Fibrosis by Modulating Mitochondrial Pyruvate Metabolism.

ABSTRACT: A hepatic comorbidity of metabolic syndrome, known as nonalcoholic fatty liver disease (NAFLD), is increasing in prevalence in conjunction with the pandemics of obesity and diabetes. The spectrum of NAFLD ranges from simple hepatic fat accumulation to a more severe disease termed nonalcoholic steatohepatitis (NASH), involving inflammation, hepatocyte death, and fibrosis. Importantly, NASH is linked to a much higher risk of cirrhosis, liver failure, and hepatocellular carcinoma, as well as an increased risk for nonhepatic malignancies and cardiovascular disease. Interest in the understanding of the disease processes and search for treatments for the spectrum of NAFLD-NASH has increased exponentially, but there are no approved pharmacologic therapies. In this review, we discuss the existing literature supporting insulin-sensitizing thiazolidinedione compounds as potential drug candidates for the treatment of NASH. In addition, we put these results into new context by summarizing recent studies suggesting these compounds alter mitochondrial metabolism by binding and inhibiting the mitochondrial pyruvate carrier.

SUBMITTER: McCommis KS

PROVIDER: S-EPMC6352854 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Treating Hepatic Steatosis and Fibrosis by Modulating Mitochondrial Pyruvate Metabolism.

McCommis Kyle S KS Finck Brian N BN

Cellular and molecular gastroenterology and hepatology 20181010 2

A hepatic comorbidity of metabolic syndrome, known as nonalcoholic fatty liver disease (NAFLD), is increasing in prevalence in conjunction with the pandemics of obesity and diabetes. The spectrum of NAFLD ranges from simple hepatic fat accumulation to a more severe disease termed nonalcoholic steatohepatitis (NASH), involving inflammation, hepatocyte death, and fibrosis. Importantly, NASH is linked to a much higher risk of cirrhosis, liver failure, and hepatocellular carcinoma, as well as an inc ...[more]

PMID: 30686780

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Project description:PurposeThe purpose of this study was to critically test the hypothesis that mitochondrial pyruvate carrier (MPC) function is essential for maintenance of the corneal myofibroblast phenotype in vitro and in vivo.MethodsProtein and mRNA for canonical profibrotic markers were assessed in cultured cat corneal myofibroblasts generated via transforming growth factor (TGF)-β1 stimulation and treated with either the thiazolidinedione (TZD) troglitazone or the MPC inhibitor alpha-cyano-beta-(1-phenylindol-3-yl) acrylate (UK-5099). RNA sequencing was used to gain insight into signaling modules related to instructive, permissive, or corollary changes in gene expression following treatment. A feline photorefractive keratectomy (PRK) model of corneal wounding was used to test the efficacy of topical troglitazone at reducing α-smooth muscle actin (SMA)-positive staining when applied 2 to 4 weeks postoperatively, during peak fibrosis.ResultsTroglitazone caused cultured myofibroblasts to adopt a fibroblast-like phenotype through a noncanonical, peroxisome proliferator-activated receptor (PPAR)-γ-independent mechanism. Direct MPC inhibition using UK-5099 recapitulated this effect, but classic inhibitors of oxidative phosphorylation (OXPHOS) did not. Gene Set Enrichment Analysis (GSEA) of RNA sequencing data converged on energy substrate utilization and the Mitochondrial Permeability Transition pore as key players in myofibroblast maintenance. Finally, troglitazone applied onto an established zone of active fibrosis post-PRK significantly reduced stromal α-SMA expression.ConclusionsOur results provide empirical evidence that metabolic remodeling in myofibroblasts creates selective vulnerabilities beyond simply mitochondrial energy production, and that these are critical for maintenance of the myofibroblast phenotype. For the first time, we provide proof-of-concept data showing that this remodeling can be exploited to treat existing corneal fibrosis via inhibition of the MPC.

Dataset Information

Treating Hepatic Steatosis and Fibrosis by Modulating Mitochondrial Pyruvate Metabolism.

Publications

Treating Hepatic Steatosis and Fibrosis by Modulating Mitochondrial Pyruvate Metabolism.

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