Insulin Resistance and Vulnerability to Cardiac Ischemia.

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 nonalcoholic 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 (AMIs). Whereas indexes of left ventricle (LV) contraction were similar in both groups at baseline, NAFLD-IR showed severe myocardial dysfunction post-AMI, with prominent LV reshaping and increased end-diastolic and end-systolic 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. The diacylglycerol-PKCε pathway and reduced mitochondrial efficiency both caused by myocardial lipotoxicity may contribute to the impaired LV compensation of the noninfarcted region of the myocardium.

• Authors: Tomas Jelenik, Ulrich Flögel, Elisa Álvarez-Hernández, Daniel Scheiber, Elric Zweck, Zhaoping Ding, Maik Rothe, Lucia Mastrototaro, Vivien Kohlhaas, Jörg Kotzka, Birgit Knebel, Dirk Müller-Wieland, Sarah Moellendorf, Axel Gödecke, Malte Kelm, Ralf Westenfeld, Michael Roden, Julia Szendroedi
• Journal: Diabetes (Diabetes) Vol. 67 Issue 12 Pg. 2695-2702 (12 2018) ISSN: 1939-327X [Electronic] United States
• PMID: 30257974 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by the American Diabetes Association.

Topics

• Animals
• Disease Models, Animal
• Humans
• Insulin Resistance (physiology)
• Mice
• Mitochondria, Heart (metabolism)
• Myocardial Infarction (complications, metabolism)
• Myocardium (metabolism)
• Non-alcoholic Fatty Liver Disease (complications, metabolism)
• Oxidative Stress (physiology)