The Impact of Lrat on Cardiomyocyte Energetics and Survival
Final Report Abstract
Perturbed mitochondrial energetics and vitamin A metabolism are associated with the pathogenesis of type 2 diabetes (T2D). To test the hypothesis that vitamin A regulates tissuespecific mitochondrial energetics and adverse organ remodeling in diet-induced obesity (DIO), we subjected mice with Lecithin retinol acyltransferase (Lrat) germline deletion, which exhibit impaired vitamin A stores, to vitamin A-deficient high fat diet (HFD) feeding. Wildtype mice fed with a vitamin A-sufficient HFD served as controls. Mitochondrial respiratory capacity and organ remodeling were assessed in cardiac, liver, skeletal muscle, and kidney tissue, which are major targets of T2D-associated complications and are critical for the pathogenesis of T2D. Cardiac structure, contractile function, and mitochondrial respiratory capacity were preserved despite vitamin A-deficiency following 20 weeks of HFD feeding. Gene profiling by RNA sequencing revealed that vitamin A is required for the expression of genes involved in cardiac fatty acid oxidation, glycolysis, tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation in DIO as expression of these genes was relatively preserved under vitamin A-sufficient HFD conditions. In liver, vitamin A had no impact on mitochondrial respiratory capacity following HFD feeding. Interestingly, histopathological and gene expression analyses revealed that vitamin A mediates steatosis and adverse remodeling in DIO. In skeletal muscle, vitamin A did not affect mitochondrial respiratory capacity following HFD feeding. No morphological differences were detected between groups. In kidney, mitochondrial respiratory capacity was not different between groups with both combinations of substrates and vitamin A transduced the pro-fibrotic transcriptional response following HFD feeding. In summary, our studies identify a transcriptional program, by which vitamin A preserves cardiac energetic gene expression in DIO that might attenuate subsequent onset of mitochondrial and contractile dysfunction. Furthermore, we identify an unexpected and tissue-specific role for vitamin A in DIO that regulates the pro-fibrotic transcriptional response and that results in organ damage independent of changes in mitochondrial energetics.
Publications
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Vitamin A preserves cardiac energetic gene expression in a murine model of diet-induced obesity. American Journal of Physiology-Heart and Circulatory Physiology, 323(6), H1352-H1364.
Naasner, Lea; Froese, Natali; Hofmann, Winfried; Galuppo, Paolo; Werlein, Christopher; Shymotiuk, Ivanna; Szaroszyk, Malgorzata; Erschow, Sergej; Amanakis, Georgios; Bähre, Heike; Kühnel, Mark P.; Jonigk, Danny D.; Geffers, Robert; Seifert, Roland; Ricke-Hoch, Melanie; Wende, Adam R.; Blaner, William S.; Abel, E. Dale; Bauersachs, Johann & Riehle, Christian
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Vitamin A Preserves Cardiac Energetic Gene Expression in a Murine Model of Diet-Induced Obesity. Jahrestagung Deutsche Gesellschaft für Kardiologie, Mannheim. Postervortrag. Clinical Research in Cardiology (2023) 112:100; P960.
Naasner L., Froese N., Galuppo P., Werlein C., Szaroszyk M., Erschow S., Kühnel M.P., Jonigk D.D., Geffers G., Ricke-Hoch M., Bauersachs J. & Riehle C.
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Vitamin A regulates tissue-specific organ remodeling in diet-induced obesity independent of mitochondrial function. Frontiers in Endocrinology, 14.
Shymotiuk, Ivanna; Froese, Natali; Werlein, Christopher; Naasner, Lea; Szaroszyk, Malgorzata; Kühnel, Mark P.; Jonigk, Danny D.; Blaner, William S.; Wende, Adam R.; Abel, E. Dale; Bauersachs, Johann & Riehle, Christian
