LIPIN 1 AND CARDIAC METABOLISM IN THE CONTEXT OF LIPID OVERLOAD

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Lipin 1 is emerging as a critical regulator of intermediary metabolism. Lipin 1 connects mitochondrial metabolic homeostasis to glycerolipid metabolism through its bi-functional molecular activities. We have shown that lipin 1 acts in the nucleus to regulate the expression of genes encoding mitochondrial enzymes by interacting with DNA-bound transcription factors and coactivators. However, lipin 1 can rapidly translocate within the cell and also acts as a lipid phosphatase at the endoplasmic reticulum (ER) membrane to dephosphorylate phosphatidic acid (PA) to form diacylglycerol (DAG); a key step in glycerolipid metabolism and triglyceride synthesis. Evidence has emerged that lipin 1 activity is highly influenced via serine/threonine phosphorylation by the molecular target of rapamycin complex 1 (mTORC1) and by the concentration of fatty acids and PA in the cell, which together regulate the sub-cellular localization of lipin 1. This allows lipin 1 to regulate both anabolic an catabolic pathways depending upon the nutrient availability of the cell. We hypothesize that chronic caloric and lipid excess will lead to increased phosphorylation and cytoplasmic localization of lipin 1. We also hypothesize that abnormalities in the regulation of cardiac lipin activity promote glycerolipid synthesis and inhibit its pro-catabolic actions, contributing to the lipotoxic cardiomyopathy that develops in states of chronic caloric excess. There are three primary goals of this application. 1. To determine the effects of dietary nutrient manipulation on cardiac myocyte lipin 1 expression, activity, and sub-cellular localization. 2. To determine whether genetic alterations in nuclear and cytoplasmic lipin 1 activity will modulate lipotoxic cardiomyopathy and impact cardiac lipid metabolism, signaling, and function. 3. To evaluate the effects of altered lipin 1 activity on the response to ischemia-reperfusion injury, which is impaired in diabetic heart. These goals will be achieved by using a variety of transgenic mouse models with altered cardiac lipin 1 activity. The effects of modulating cardiac lipin 1 activity wil be assessed by using sophisticated functional phenotyping, transcriptomics, and lipidomics. The use of these -omic approaches is anticipated to identify a cardiac signature for identifying biomarkers linked to development or protection from dysfunction in obese hearts. The overarching goal will then be to use this information to benefit human subjects with diabetic heart disease.