Overwhelming evidence links obesity with increased risk for several chronic diseases including non- alcoholic fatty liver disease (NAFLD). The condition, NAFLD, encompasses both simple hepatic steatosis and the more severe non-alcoholic steatohepatitis (NASH;hepatic inflammation and fibrosis associated with steatotic lesions). With the epidemic of obesity in the U.S., the occurrence of NAFLD has risen exuberantly, becoming the most common cause of liver disease. Although steatohepatitis can progress to cirrhosis and liver failure, the most common co-morbidity of NAFLD is hepatic insulin resistance and systemic abnormalities in circulating glucose, lipid, and inflammatory mediator concentrations. A complete understanding of the factors that influence the development and progression of NAFLD is needed. Recent work has suggested that the lipin family of proteins (lipin 1, 2, and 3) coordinate and connect hepatic mitochondrial and glycerolipid metabolism through their bifunctional molecular activities. Lipins are metabolic enzymes that dephosphorylate phosphatidic acid (PA) to form diacylglycerol (DAG) (PAP activity) at the endoplasmic reticulum membrane, but also act in the nucleus to regulate the expression of genes encoding mitochondrial enzymes by interacting with DNA-bound transcription factors. We have serendipitously generated a mouse model that will allow us to distinguish the two molecular functions of lipin 1 in liver. The studies proposed herein are designed to: [1] characterize and distinguish the nucleocytoplasmic effects of lipin 1 in hepatocytes, [2] to determine whether lipin 2 also has transcriptional regulatory function and define the genomic profile of its targets, and [3] to define the compensatory mechanisms facilitating hepatic triglyceride synthesis in the context of diminished PAP activity. The results f these studies will not only have implications for our understanding of the biology of lipin proteins, but will also provide new insight into the basic molecular regulation of intermediary metabolism.

Public Health Relevance

The increasing prevalence of obesity is driving a surge in the incidence of associated metabolic diseases of the liver including non-alcoholic fatty liver disease (NAFLD). We believe that understanding how the family of lipin proteins control hepatic fatty acid metabolism may be important for the development of new therapies to treat patients with NAFLD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK078187-06A1
Application #
8436991
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Pawlyk, Aaron
Project Start
2007-04-01
Project End
2017-01-31
Budget Start
2013-02-25
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$330,600
Indirect Cost
$113,100
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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