COBRE Pilot Project for Hongmei Ren: Center for Research in Obesity and Cardiovascular Disease

Lipin1, encoded by the LPIN1 gene, is a phosphatidic acid phosphatase enzyme that catalyzes the penultimate step in triglyceride synthesis. Lipin1 is also a nuclear transcriptional coactivator of PPARá, and thereby selectively activates a subset of PGC-1á target pathways. Our preliminary data and observations from others also suggest a new facet of lipin1 to regulate mitochondrial fatty acid oxidation. Our recent observation shows that lipin1 is recruited to the surface of mitochondria and converts phosphatidic acid (PA) to diacylglycerol (DG) and promotes mitochondria fission. My COBRE research proposal is designed to define the role of lipin1 in mitochondrial function, skeletal muscle physiology and whole body energy expenditure. The proposed research becomes even more significant by the recent discovery that lipin1 mutations in humans are a cause of infant rhabdomyolysis (skeletal muscle degeneration). This condition is commonly associated with mitochondrial dysfunction. Although we observed that lipin1 deficient mice have decreased carnitine palmitoyl transferase activity, impaired fatty acid â-oxidation in skeletal muscle which is consistent with human harboring lipin1 mutants, these mice do not show obvious muscle degeneration defect. The reason for this difference is not yet clear but may involve fundamental differences in the regulation and function of the mouse lipin1 (mlipin1) and human lipin1 (hlipin1) orthologs or the functional consequence induced by hlipin1 mutants. Since the majority of published studies so far have focused on the role of mlipin1 by using lipin1 deficient fld mice, the function of hlipin1 has not been fully explored. The objective of this study is to use cell culture system to compare the role of hlipin1 and mlipin1 in mitochondrial lipid composition and function, skeletal myogenesis and muscle regeneration function. We will also focus on studying hlipin1 by identifying the functional impacts of hlipin1 mutants on lipin1.