@article{51d978d28f45471f9dab94fb8fda8402,
title = "Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease",
abstract = "Objective: Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. Here we investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation. Methods: Hepatic insulin sensitivity, endogenous glucose production, and mitochondrial metabolic fluxes were determined in wild-type, obese (ob/ob) and pioglitazone-treatment obese mice using a combination of radiolabeled tracer and stable isotope NMR approaches. Mechanistic studies of pioglitazone action were performed in isolated primary hepatocytes, whilst molecular hepatic lipid species were profiled using shotgun lipidomics. Results: Livers from obese, insulin-resistant mice displayed augmented mitochondrial content and increased tricarboxylic acid cycle (TCA) cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with pioglitazone mitigated pyruvate-driven TCA cycle activity and PDH activation via both allosteric (intracellular pyruvate availability) and covalent (PDK4 and PDP2) mechanisms that were dependent on PPARγ activity in isolated primary hepatocytes. Improved mitochondrial function following pioglitazone treatment was entirely dissociated from changes in hepatic triglycerides, diacylglycerides, or fatty acids. Instead, we highlight a role for the mitochondrial phospholipid cardiolipin, which underwent pathological remodeling in livers from obese mice that was reversed by insulin sensitization. Conclusion: Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.",
keywords = "Cardiolipin, Insulin resistance, Metabolic liver disease, Mitochondria, Pyruvate dehydrogenase, Thiazolidinedione",
author = "Shannon, {Chris E.} and Mukundan Ragavan and Palavicini, {Juan Pablo} and Marcel Fourcaudot and Bakewell, {Terry M.} and Valdez, {Ivan A.} and Iriscilla Ayala and Jin, {Eunsook S.} and Muniswamy Madesh and Xianlin Han and Merritt, {Matthew E.} and Luke Norton",
note = "Funding Information: Project supported by funding from the University of Florida{\textquoteright}s Southeast Center for Integrated Metabolomics through grant number U24DK097209 from the National Institute of Health{\textquoteright}s Common Fund metabolomics program . A portion of this work was performed at the National High Magnetic Field Laboratory, which is supported by National Science Foundation Cooperative Agreement number DMR1644779 , & the State of Florida, NIH P41-122698, and NIH R01-105346. Additional experiments were performed at Advanced Imaging Center at the University of Texas Southwestern Medical Center, which was supported by an NIH grant P41EB015908 . C.E.S. is supported by an UT Health San Antonio OPA Postdoctoral Research Fellowship . A portion of this work was supported by A merican Diabetes Association Grant 1-15-MI-07 (X.H and J.P.P). Funding Information: Project supported by funding from the University of Florida's Southeast Center for Integrated Metabolomics through grant number U24DK097209 from the National Institute of Health's Common Fund metabolomics program. A portion of this work was performed at the National High Magnetic Field Laboratory, which is supported by National Science Foundation Cooperative Agreement number DMR1644779, & the State of Florida, NIH P41-122698, and NIH R01-105346. Additional experiments were performed at Advanced Imaging Center at the University of Texas Southwestern Medical Center, which was supported by an NIH grant P41EB015908. C.E.S. is supported by an UT Health San Antonio OPA Postdoctoral Research Fellowship. A portion of this work was supported by American Diabetes Association Grant 1-15-MI-07 (X.H and J.P.P). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2021",
month = mar,
doi = "10.1016/j.molmet.2020.101154",
language = "English (US)",
volume = "45",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
}