Sex-Dependent Increases of Hepatic Acylcarnitines by Myocardial Infarction

Abstract

Many different diseases and environmental stressors can lead to an increase in oxidative stress. Urban air pollution leads to inhalation of airborne particulate matter in high traffc environments. This has been linked to chronic oxidative stress and increased risk or severity of myocardial infarction (MI). MI is one cause of acute oxidative stress. A key player for cellular defense against oxidative stress is activation of Nrf2, a transcription factor that controls the expression of key antioxidant and cytoprotective genes. Although Nrf2 has been reported to regulate genes for anabolic or lipid metabolism, little is known about the impact of Nrf2 or MI on the biochemical metabolism in the liver. Because the liver is a center for metabolism, metabolomic landscapes were determined in a model of chronic oxidative stress by Nrf2 knockout or acute oxidative stress by induction of MI via left anterior descending coronary artery ligation. 1353 compounds were detected with a quality control coeffcient variation value <20% using LC-MS/MS based non-targeted metabolomics. Differences in the baseline metabolic profiles of male versus female lead to comparison of Nrf2 knockout or MI in a sex specific manner. In male wild type mice, the liver responded to MI by elevating several carnitine derivatives, including linoleoyl carnitine, palmitoyl carnitine, and (11Z, 14Z)-eicosadienoyl carnitine. However, none of these changes were observed in female wild type mice. Either male or female Nrf2 knockout mice failed to respond to MI by elevating carnitines. These acylcarnitine increases were confirmed with a non-targeted lipidomics analysis. The elevated acylcarnitine levels correlate with an increase in carnitine palmitoyl transferase 1, CPT1, the enzyme responsible for the conjugation of carnitine and long-chain fatty acids. After this conjugation, acylcarnitines are transported into the mitochondria via carnitine-acylcarnitine translocase. Once inside the mitochondria, the carnitine moiety is removed via CPT2 and the long-chain fatty acid can be used for beta-oxidation to produce ATP. This data suggest that male mice are responding to MI by altering energy metabolism and increasing carnitines to compensate for energy production. Nrf2 appears to play a role in such metabolic reprogramming. The research programs under the direction of Dr. Qin M. Chen have been supported by NIH R01 GM125212, R01 GM126165, Holsclaw Endowment, the University of Arizona College of Pharmacy start-up fund, and NIEHS T32 ES007091. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.