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.

Public Health Relevance

Abnormalities in cardiac metabolism are known to lead to cardiac dysfunction and heart failure. We have preliminary evidence that a protein called lipin 1 is an important regulator of energy and lipid metabolism. The goal of this application is to better understand the role of lipin 1 in regulating cardiac metabolism in the diabetic heart. This goal could allow for the identification of new therapies for treating cardiac disease in people with diabetes, which is extremely common.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL119225-02
Application #
8916176
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2014-08-22
Project End
2018-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Schweitzer, George G; Collier, Sara L; Chen, Zhouji et al. (2018) Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. FASEB J :fj201800361R
Lutkewitte, Andrew J; Schweitzer, George G; Kennon-McGill, Stefanie et al. (2018) Lipin deactivation after acetaminophen overdose causes phosphatidic acid accumulation in liver and plasma in mice and humans and enhances liver regeneration. Food Chem Toxicol 115:273-283
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