Jelenik 2018 Diabetes
|Jelenik T, Flögel U, Álvarez-Hernández E, Scheiber D, Zweck E, Ding Z, Rothe M, Mastrototaro L, Kohlhaas V, Kotzka J, Knebel B, Müller-Wieland D, Moellendorf S, Gödecke A, Kelm M, Westenfeld R, Roden M, Szendroedi J (2018) Insulin resistance and vulnerability to cardiac ischemia. Diabetes 67:2695-702.|
Jelenik T, Floegel U, Alvarez-Hernandez E, Scheiber D, Zweck E, Ding Z, Rothe M, Mastrototaro L, Kohlhaas V, Kotzka J, Knebel B, Mueller-Wieland D, Moellendorf S, Goedecke A, Kelm M, Westenfeld R, Roden M, Szendroedi J (2018) Diabetes
Abstract: Hepatic and myocardial ectopic lipid deposition has been associated with insulin resistance (IR) and cardiovascular risk. Lipid overload promotes increased hepatic oxidative capacity, oxidative stress and impaired mitochondrial efficiency, driving the progression of non-alcoholic fatty liver disease (NAFLD). We hypothesized that higher lipid availability promotes ischemia-induced cardiac dysfunction and decreases myocardial mitochondrial efficiency. Mice with adipose tissue-specific overexpression of sterol-element-binding protein 1c as model of lipid overload with combined NAFLD-IR and controls underwent reperfused acute myocardial infarcts (AMI). While indexes of left ventricle contraction were similar in both groups at baseline, NAFLD-IR showed severe myocardial dysfunction post-AMI with prominent left ventricular reshaping and increased enddiastolic and endsystolic volumes. Hearts of NAFLD-IR displayed hypertrophy, steatosis and IR due to 18:1/18:1-diacylglycerol-mediated protein kinase Cε (PKCε) activation. Myocardial fatty acid-linked respiration and oxidative stress were increased, whereas mitochondrial efficiency was decreased. In humans, decreased myocardial mitochondrial efficiency of ventricle biopsies related to IR and troponin levels, a marker of impaired myocardial integrity. Taken together, increased lipid-availability and IR favor susceptibility to ischemia-induced cardiac dysfunction. Diacylglycerol-PKCε pathway and reduced mitochondrial efficiency both caused by myocardial lipotoxicity may contribute to the impaired left ventricular compensation of the non-infarcted region of the myocardium.
• Keywords: Myocardial infarction, Non-insulin treated type 2 diabetes, Cardiac ischemia, Insulin resistance, Ectopic lipids, Cardiac steatosis, Cardiac hypertrophy, Mitochondrial function • Bioblast editor: Plangger M • O2k-Network Lab: DE Duesseldorf Roden M
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Cardiovascular, Diabetes Stress:Ischemia-reperfusion Organism: Human, Mouse Tissue;cell: Heart Preparation: Permeabilized tissue, Isolated mitochondria
Regulation: Fatty acid Coupling state: LEAK, OXPHOS Pathway: F, N, NS, ROX HRR: Oxygraph-2k, O2k-Fluorometer