title: Impaired Cardiolipin Biosynthesis Prevents Hepatic Steatosis and Diet-Induced Obesity.
abstract: Mitochondria are the nexus of energy metabolism, and consequently their dysfunction has been implicated in the development of metabolic complications and progression to insulin resistance and type 2 diabetes. The unique tetra-acyl phospholipid cardiolipin (CL) is located in the inner mitochondrial membrane, where it maintains mitochondrial integrity. Here we show that knockdown of Tafazzin (TAZ kd), a CL transacylase, in mice results in protection against the development of obesity, insulin resistance, and hepatic steatosis. We determined that hypermetabolism protected TAZ kd mice from weight gain. Unexpectedly, the large reduction of CL in the heart and skeletal muscle of TAZ kd mice was not mirrored in the liver. As a result, TAZ kd mice exhibited normal hepatic mitochondrial supercomplex formation and elevated hepatic fatty acid oxidation. Collectively, these studies identify a key role for hepatic CL remodeling in regulating susceptibility to insulin resistance and as a novel therapeutic target for diet-induced obesity.
authors: Children's Hospital Research Institute of Manitoba, Department of Pharmacology & Therapeutics, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
authors: Laura K
authors: LK
authors: Cole
authors: Children's Hospital Research Institute of Manitoba, Department of Pharmacology & Therapeutics, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
authors: Edgard M
authors: EM
authors: Mejia
authors: Children's Hospital Research Institute of Manitoba, Department of Pharmacology & Therapeutics, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
authors: Marilyne
authors: M
authors: Vandel
authors: Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO.
authors: Genevieve C
authors: GC
authors: Sparagna
authors: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors: Steven M
authors: SM
authors: Claypool
authors: Children's Hospital Research Institute of Manitoba, Department of Pharmacology & Therapeutics, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
authors: Laura
authors: L
authors: Dyck-Chan
authors: Diagnostic Services of Manitoba, Winnipeg, Canada.
authors: Julianne
authors: J
authors: Klein
authors: Children's Hospital Research Institute of Manitoba, Department of Pharmacology & Therapeutics, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada ghatch@chrim.ca.
authors: Grant M
authors: GM
authors: Hatch
mesh_terms: D000217:Acyltransferases; D000818:Animals; D015153:Blotting, Western; D002308:Cardiolipins / Q000096:biosynthesis* / Q000378:metabolism*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism; D015430:Weight Gain / Q000235:genetics / Q000502:physiology
chemical_list: D002308:Cardiolipins; D014157:Transcription Factors; D000217:Acyltransferases; C486363:tafazzin protein, mouse