PROJ 3: ROLE OF SHP IN FATTY LIVER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The current obesity epidemic is resulting in a dramatic increase in the metabolic syndrome, that frequently results in fatty liver, which can cause fibrosis, cirrhosis, and end-stage liver disease. Obesity affects 64% of the U.S. population and results in 300,000 deaths every year. Fatty liver (steatosis) associated with obesity affects more than 50% of people over the age of 50. The goal of these studies is to understand the role that the orphan nuclear receptor small heterodimer partner (SHP) plays in the molecular mechanisms of dyslipidemias associated with fatty liver. Eliminating SHP signaling, in SHP-null mice, protects against a high cholesterol or high-fat diet induced liver steatosis and obesity. Intriguingly, the fatty liver in leptin deficient obese mice (OB/OB) was also prevented by the absence of SHP (OB/SHP-double-null mice). This provides a unique animal model to explore the function of SHP in fatty liver formation. The hypothesis to be tested is that SHP functions to modulate the expression of critical steps in lipid metabolism, and that SHP regulated pathways are essential for the development of fatty liver. To test this hypothesis, the following specific aims will be addressed: 1) Determine whether decreased serum triglyceride clearance and hepatic lipid uptake or increased hepatic VLDL production occurs in OB/SHP-null mice; 2) Characterize expression of genes involved in lipoprotein transport (e.g., VLDL production, HDL synthesis, triglyceride clearance, lipid uptake, and hepatic lipid synthesis) in OB/OB and OB/SHP-null mice to identify SHP target genes; 3) Identify SHPregulated-target genes in hepatic lipid metabolic pathways, and examine the transcriptional regulation of these genes by SHP, to determine the mechanism that prevents fatty liver in OB/SHP-null mice. Identifying the specific functions of SHP and the underlying mechanisms that account for the prevention of fatty liver in OB/SHP-null mice, will provide mechanistic insight and novel approaches to understanding and preventing obesity-associated fatty liver in patients.