Grants and Contracts Details
Obesity is a disorder of energy balance in which dietary consumption of carbohydrates and fats exceeds their rate of catabolism. Storage of unexpended fuels as triglycerides results in an expansion of visceral adipose tissue and has a broader impact on the lipid composition of cells and tissues resulting in susceptibility to cardiovascular and metabolic disease. Mitochondria play a central role in energy homeostasis, generating ATP by oxidative metabolism of carbohydrates and fatty acids. Mitochondria are membranous organelles containing proteins that are encoded in part by their intrinsic DNA and in part by nuclear genes. Mitochondria divide by binary fission which ensures transfer of mitochondria to a daughter cell during cell division. In conjunction with transcriptional regulation of mitochondrial protein expression this process also dictates the number and size of mitochondria in a cell, coordinating the demand for aerobic respiration with energy status. The lipid composition of mitochondria is distinct and lipids regulate mitochondrial oxidative metabolism and homeostasis through effects on mitochondrial fusion and fission and on the activity of mitochondrial membrane proteins. We found that a master metabolic regulator called lipin1 is recruited to the surface of mitochondria where it participates in a signaling pathway that promotes mitochondrial fission and remodels mitochondrial lipids. Lipin1 is a phosphatidic acid (PA) phosphatase enzyme that catalyzes the penultimate step in triglyceride synthesis at the cytoplasmic surface of the endoplasmic reticulum and also serves as a nuclear transcriptional co-activator of PPAR-alpha; responsive genes. Fatty acid oxidation is markedly impaired in lipin1 deficient mice and humans. We therefore hypothesize that localization of lipin1 to mitochondria promotes oxidative metabolism through effects on mitochondrial homeostasis and lipid composition. We will test this hypothesis by defining the mechanism of lipin1 recruitment to the mitochondrial surface and determining the role of lipin1 in regulation of mitochondrial oxidative metabolism using cell culture models and isolated heart tissue. Completion of this work would establish lipn1 as a novel mechanistic link between the counter regulatory processes of triglyceride synthesis and fatty acid oxidation.
|Effective start/end date||7/1/12 → 6/30/13|
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