Body weight is determined by the balance between energy input and expenditure. Skeletal muscle is major site of mitochondrial oxidative metabolism of fatty acids and glucose and thereby plays a central role in whole body energy expenditure. Accordingly, preservation or promotion of skeletal muscle metabolism could play a critical role in protection from diet induced obesity. Understanding the mechanisms that regulate skeletal muscle metabolism and their relationship to those controlling fatty storage and mobilization is therefore a critical goal in metabolic disease research. Lipinl 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-a responsive genes. Lipinl deficient mice (fatty liver dystrophy mice, fid mice) exhibit impaired adipocyte differentiation, circulating hyperlipidemia and neonatal hepatic steatosis associated with diminished rates of hepatic fatty acid oxidation. Lipinl is also expressed in skeletal muscle and transgenic overexpression of lipinl in this tissue reverses many ofthe phenotypes of lipinl deficient fid mice. Interestingly, humans with heritable lipinl null mutations present with severe rhabdomyolysis (skeletal, muscle degeneration) characterized by impaired carnitine palmitoyi acyltransferase (CPT) activity, decreased mitochondrial fatty oxidation and respiratory chain function and the consequent destruction of skeletal muscle fibers. We made the seminal observation that lipinl is recruited to the mitochondrial surface where it promotes mitochondrial fission and remodels mitochondrial lipids, suggesting that lipinl deficiency impacts directly on mitochondrial function. Based on these observations we propose that lipinl is poised to function as a link between fatty acid and carbohydrate metabolism in muscle and fat. Accordingly, we hypothesize that recruitment of lipinl to mitochondria directly promotes mitochondrial respiratory function and beta-oxidation through effects on mitochondrial homeostasis and lipid composition and that this is particularly important for skeletal muscle function in energy metabolism. In direct support of our hypothesis, we found mitochondrial respiratory function is impaired in lipinl deficient mouse embryo fibroblasts and mitochondria isolated from skeletal muscle of lipinl deficient rnice. The broad goal of this research is to define the role of Lipinl in mitochondrial function and skeletal muscle physiology.
Aim 1 defines the role of muscle cell lipinl PA phosphatase activity in regulating mitochondrial lipid composition and function, while Aim 2 examines deletion of skeletal muscle lipinl in lean and obese mice.

Public Health Relevance

Lipin l is emerging as a master regulator of metabolism. Inter-individual variation in lipinl expression and alterations in lipinl mRNA processing have been associated with human susceptibility to diet induced obesity. Our proposed studies promise to reveal a new facet of lipinl function in skeletal muscle and to define the role of lipinl as a link between fat storage in adipose tissue and consumption of mobilized fatty acids by skeletal muscle mitochondrial oxidative metabolism.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-TWD-Y)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
United States
Zip Code
Crack, Peter J; Zhang, Moses; Morganti-Kossmann, Maria Cristina et al. (2014) Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes. J Neuroinflammation 11:37
Liu, Xiaoxi; Liu, Jingjing; Liang, Shuang et al. (2014) ABCD2 alters peroxisome proliferator-activated receptor ? signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity. Mol Pharmacol 86:505-13
Su, Kai; Sabeva, Nadezhda S; Wang, Yuhuan et al. (2014) Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice. Arterioscler Thromb Vasc Biol 34:26-33
Wang, Fengbin; Singh, Shanteri; Zhang, Jianjun et al. (2014) Understanding molecular recognition of promiscuity of thermophilic methionine adenosyltransferase sMAT from SulfolobusĀ solfataricus. FEBS J 281:4224-39
Shaaban, Khaled A; Singh, Shanteri; Elshahawi, Sherif I et al. (2014) Venturicidin C, a new 20-membered macrolide produced by Streptomyces sp. TS-2-2. J Antibiot (Tokyo) 67:223-30
Newsome, Bradley J; Petriello, Michael C; Han, Sung Gu et al. (2014) Green tea diet decreases PCB 126-induced oxidative stress in mice by up-regulating antioxidant enzymes. J Nutr Biochem 25:126-35
Zhang, Jianjun; Singh, Shanteri; Hughes, Ryan R et al. (2014) A simple strategy for glycosyltransferase-catalyzed aminosugar nucleotide synthesis. Chembiochem 15:647-52
Liu, M; Alimov, A P; Wang, H et al. (2014) Thiamine deficiency induces anorexia by inhibiting hypothalamic AMPK. Neuroscience 267:102-13
Jiang, Erlie; Perrard, Xiaoyuan Dai; Yang, Donglin et al. (2014) Essential role of CD11a in CD8+ T-cell accumulation and activation in adipose tissue. Arterioscler Thromb Vasc Biol 34:34-43
Shridas, Preetha; Zahoor, Lubna; Forrest, Kathy J et al. (2014) Group X secretory phospholipase A2 regulates insulin secretion through a cyclooxygenase-2-dependent mechanism. J Biol Chem 289:27410-7

Showing the most recent 10 out of 45 publications