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COCVD INVESTIGATORS
PILOT PROJECT
The role of human lipin1 in skeletal muscle function
 Hongmei
Ren, Ph.D.
Assistant Professor
Division of Cardiology
Department of Internal Medicine
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. 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-α responsive genes. Lipin1
deficient mice (fatty liver dystrophy mice, fld mice) exhibit impaired adipocyte
differentiation, circulating hyperlipidemia and neonatal hepatic steatosis
associated with diminished rates of hepatic fatty acid oxidation. Lipin1 is also
expressed in skeletal muscle and transgenic overexpression of lipin1 in this
tissue reverses many of the phenotypes of lipin1 deficient fld mice.
Interestingly, humans with heritable lipin1 null mutations present with severe
rhabdomyolysis (skeletal muscle degeneration) characterized by impaired
carnitine palmitoyl 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 lipin1 is recruited
to the mitochondrial surface where it promotes mitochondrial fission and
remodels mitochondrial lipids, suggesting that lipin1 deficiency impacts
directly on mitochondrial function. Based on these observations we propose that
lipin1 is poised to function as a link between fatty acid and carbohydrate
metabolism in muscle and fat.
Accordingly, we hypothesize that recruitment of lipin1 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
lipin1 deficient mouse embryo fibroblasts and mitochondria isolated from
skeletal muscle of lipin1 deficient mice. The broad goal of this research is to
define the role of Lipin1 in mitochondrial function and skeletal muscle
physiology. Aim 1 defines the role of
muscle cell lipin1 PA phosphatase activity in regulating mitochondrial lipid
composition and function, while Aim 2 examines deletion of skeletal muscle
lipin1 in lean and obese mice.
PROJECT MENTORS
 Philip
Kern, M.D.
Professor, Division of Endocrinology
Director of Barnstable Brown Kentucky Diabetes and Obesity Center
Director
Center of Clinical and Translational Science
Department of Internal Medicine
 Andrew
Morris, Ph.D.
Professor
Division of Cardiology
Division of Molecular and Cellular Biochemistry
Department of
Internal Medicine
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