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Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

The orphan receptor Small Heterodimer Partner (SHP, NROB2) regulates metabolic pathways, including hepatic bile acid, lipid, and glucose homeostasis. We reported that SHP‐deletion in leptin‐deficient OB−/− mice increases insulin sensitivity, and prevents the development of fatty liver. The prevention of steatosis in OB−/−/SHP−/− double mutants is not due to decreased body weight but is associated with increased hepatic very‐low‐density lipoprotein (VLDL) secretion and elevated microsomal triglyceride transfer protein (MTP) mRNA and protein levels. SHP represses the transactivation of the MTP promoter and the induction of MTP mRNA by LRH‐1 in hepatocytes. Adenoviral overexpression of SHP inhibits MTP activity as well as VLDL‐apoB protein secretion, and RNAi knockdown of SHP exhibits opposite effects. The expression of SHP in induced in fatty livers of OB−/− mice and other genetic or dietary models of steatosis, and acute overexpression of SHP by adenovirus, result in rapid accumulation of neutral lipids in hepatocytes. In addition, the pathways for hepatic lipid uptake and lipogenic program are also downregulated in OB−/−/SHP−/− mice, which may contribute to the decreased hepatic lipid content. Conclusion: These studies demonstrate that SHP regulates the development of fatty liver by modulating hepatic lipid export, uptake, and synthesis, and that the improved peripheral insulin sensitivity in OB−/−/SHP−/− mice is associated with decreased hepatic steatosis. (HEPATOLOGY 2007.)