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Abstract Details
Insulin Resistance is Mechanistically Linked to Hepatic Mitochondrial Remodeling in Nonalcoholic Fatty Liver Disease
Mol Metab. 2020 Dec 22;101154. doi: 10.1016/j.molmet.2020.101154. Online ahead of print.
Chris E Shannon1, Mukundan Ragavan2, Juan Pablo Palavicini3, Marcel Fourcaudot1, Terry Bakewell1, Ivan A Valdez1, Iriscilla Ayala1, Eunsook S Jin4, Muniswamy Madesh5, Xianlin Han6, Matthew E Merritt2, Luke Norton7
Author information
1Division of Diabetes, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX, USA.
2Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
3Division of Diabetes, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
4Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
5Division of Nephrology, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX, USA.
6Division of Diabetes, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
7Division of Diabetes, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX, USA. Electronic address: nortonl@uthscsa.edu.
Abstract
Background: 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.
Objectives: & Approach We investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation in a rodent model of T2D/NAFLD.
Results: Livers from obese, insulin resistant mice displayed augmented mitochondrial content and increased TCA cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with the thiazolidinedione 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.
Conclusions: 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.