The current epidemic of obesity and the metabolic syndrome has dramatically increased the frequency of fatty liver, which can cause fibrosis, cirrhosis, end-stage liver disease and hepatoma. Fatty liver (steatosis) affects approximately 30 percent of the people in the USA. SHP (small heterodimer partner) is a nuclear receptor that regulates several major aspects of the metabolic syndrome, including obesity, dyslipidemia and insulin sensitivity. The major objective of this study is to determine how SHP-deficiency prevents fatty liver in mice. The central hypothesis is that SHP regulates hepatic fatty acid uptake and oxidation (Aim #1) and hepatic lipoprotein catabolism (Aim #2) in a way that has a major influence on the development of fatty liver. The loss of SHP regulation is predicted to increase lipid oxidation, and decrease lipid uptake, which coordinately decreases fat accumulation in the liver. This hypothesis is based on the Preliminary Results, demonstrating that: a) SHP deficiency in SHP-/- mice decreases hepatic lipid accumulation and protects against high-cholesterol or high-fat diet induced steatosis;b) fatty liver in obese diabetic mice (OB/OB) is prevented by the absence of SHP (OB/SHP-/- mice);c) the PPAR? pathway is down-regulated, whereas the PPARa pathway is upregulated in SHP-null mice;and d) lipoprotein clearance and HDL cholesterol uptake is decreased by SHP-deficiency. Once the mechanisms of SHP regulated transcription of critical genes in these pathways are defined, it should be possible to target these processes with small molecules to improve or prevent fatty liver disease (long-term goal).
The Specific Aims are to define: (1) mechanisms for SHP regulation of hepatic fatty acid uptake and oxidation;and, (2) mechanism for SHP regulation of lipoprotein catabolism. Identifying specific functions of SHP and the mechanisms preventing fatty liver in SHP deficient mice should provide mechanistic insight and novel approaches to treating or preventing fatty liver in patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
Zip Code
Rudraiah, Swetha; Zhang, Xi; Wang, Li (2016) Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet? Annu Rev Pharmacol Toxicol 56:605-26
Zhang, Xi; Wu, Jianguo; Choiniere, Jonathan et al. (2016) Arsenic silences hepatic PDK4 expression through activation of histone H3K9 methylatransferase G9a. Toxicol Appl Pharmacol 304:42-7
Zhang, Yuxia; Liu, Chune; Barbier, Olivier et al. (2016) Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function. Sci Rep 6:20559
Tran, Melanie; Yang, Zhihong; Liangpunsakul, Suthat et al. (2016) Metabolomics Analysis Revealed Distinct Cyclic Changes of Metabolites Altered by Chronic Ethanol-Plus-Binge and Shp Deficiency. Alcohol Clin Exp Res 40:2548-2556
Zhang, Li; Yang, Zhihong; Trottier, Jocelyn et al. (2016) LncRNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate Shp mRNA decay. Hepatology :
Yang, Zhihong; Koehler, Angela N; Wang, Li (2016) A Novel Small Molecule Activator of Nuclear Receptor SHP Inhibits HCC Cell Migration via Suppressing Ccl2. Mol Cancer Ther 15:2294-2301
Tran, Melanie; Wang, Li (2016) Preserving LXR by Inhibiting T39: A step closer to treating atherosclerosis and steatohepatitis? Hepatology :
Choiniere, Jonathan; Wang, Li (2016) Exposure to inorganic arsenic can lead to gut microbe perturbations and hepatocellular carcinoma. Acta Pharm Sin B 6:426-429
Tsuchiya, Hiroyuki; da Costa, Kerry-Ann; Lee, Sangmin et al. (2015) Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice. Gastroenterology 148:1012-1023.e14
Yang, Zhihong; Cappello, Tyler; Wang, Li (2015) Emerging role of microRNAs in lipid metabolism. Acta Pharm Sin B 5:145-50

Showing the most recent 10 out of 41 publications