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)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Lee, Sang Min; Zhang, Yuxia; Tsuchiya, Hiroyuki et al. (2015) Small heterodimer partner/neuronal PAS domain protein 2 axis regulates the oscillation of liver lipid metabolism. Hepatology 61:497-505
Zhang, Yuxia; Xu, Ningyi; Xu, Jun et al. (2014) E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network. Hepatology 60:919-30
Myronovych, Andriy; Salazar-Gonzalez, Rosa-Maria; Ryan, Karen K et al. (2014) The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice. Obesity (Silver Spring) 22:2301-11
Yang, Zhihong; Tsuchiya, Hiroyuki; Zhang, Yuxia et al. (2013) MicroRNA-433 inhibits liver cancer cell migration by repressing the protein expression and function of cAMP response element-binding protein. J Biol Chem 288:28893-9
Smalling, Rana L; Delker, Don A; Zhang, Yuxia et al. (2013) Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease. Am J Physiol Gastrointest Liver Physiol 305:G364-74
Zhang, Yuxia; Wang, Li (2013) Characterization of the mitochondrial localization of the nuclear receptor SHP and regulation of its subcellular distribution by interaction with Bcl2 and HNF4*. PLoS One 8:e68491
Yang, Zhihong; Zhang, Yuxia; Wang, Li (2013) A feedback inhibition between miRNA-127 and TGF*/c-Jun cascade in HCC cell migration via MMP13. PLoS One 8:e65256
Yang, Zhihong; Zhang, Yuxia; Wang, Li (2012) Mdm2 is a novel activator of ApoCIII promoter which is antagonized by p53 and SHP inhibition. Biochem Biophys Res Commun 417:744-6
Zhang, Yuxia; Andrews, Glen K; Wang, Li (2012) Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP. Nucleic Acids Res 40:4850-60
Zhang, Yuxia; Wang, Li (2011) Nuclear receptor SHP inhibition of Dnmt1 expression via ERR?. FEBS Lett 585:1269-75

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