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Research Description:
Summary of Research Interests:
The metabolic syndrome is a cluster of interrelated common clinical disorders,
including obesity, insulin resistance, glucose intolerance, hypertension
and dyslipidemia. In the past years, experimental evidence demonstrated crucial
roles of nuclear hormone receptors in metabolic syndrome. My laboratory is
focusing on the function of an orphan nuclear receptor small heterodimer
partner (SHP). Studies of global SHP null mice revealed that SHP is involved
in several of the primary aspects of the metabolic syndrome. Our recent finding
demonstrates that SHP regulates cell cycle progression and tumorigenesis,
thus may function as a novel tumor suppressor. The above findings suggest
important regulatory functions of SHP in obesity, diabetes, fatty liver and
cancer. Thus, this forms an integrated research program aimed at understanding
the molecular basis of how SHP regulates these important public health problems.
The current major on-going research projects in my laboratory include:
Orphan Nuclear Hormone Receptor SHP in NAFLD
NAFLD (non-alcoholic fatty liver disease) is a common chronic liver disease ranging in spectrum from steatosis without fibrosis to cirrhosis. The molecular basis for NAFLD is not well defined and therapy is difficult. The observations, that SHP-deficiency prevents fatty liver under both non-obese (SHP-/-) and obese (OB-/-/SHP-/-) conditions, emphasize the essential physiological role of SHP in the control of lipid metabolism and the development of fatty liver. The objective is to determine how SHP-deficiency prevents fatty liver in mice consuming a high-fat diet or those with diabetes and obesity. The central hypothesisis that SHP represses hepatic lipid oxidation, but activates hepatic fatty acid uptake. The loss of SHP regulation of these pathways increases lipid oxidation, but decreases lipid uptake, resulting in decreased fat accumulation in the liver. SHP activation of lipoprotein catabolism is hypothesized to provide an additional mechanism that prevents fatty liver during SHP-deficiency. Our recent study also suggests a molecular link between lipid and drug metabolism through SHP. Various single and double knockouts will be utilized for this project.
Orphan Nuclear Hormone Receptor SHP in Liver Cancer
The human hepatocellular carcinoma (HCC) is the most common primary hepatic tumor and one of the most common cancers worldwide, the molecular mechanisms of hepatocarcinogenesis are still poorly understood. The rationale for this work is based on our exciting data showing that SHP regulates cellular proliferation and tumorigenesis. In addition, SHP-/- mice developed spontaneous liver tumor, and SHP expression is markedly diminished in human HCC specimens. Moreover, the mRNA expressions of DNA methyltransferases (Dnmts) are strongly elevated in livers of SHP-/- mice, indicating an inhibitory effect by SHP. The data suggest that in addition to the role as a master metabolic regulator, SHP may also function as a novel tumor suppressor. However, the mechanism of SHP regulation of HCC remains unknown. This project focuses on identifying the function of SHP in cell proliferation, apoptosis and DNA methylation that are associated with the development of liver cancer.Orphan Nuclear Hormone Receptor SHP in microRNA Gene Regulation
MicroRNAs (miRNAs or mir) are ~22 nt non-protein-coding RNA molecules that play significant roles in the posttranscriptional repression of its target genes. Mature miRNAs are generated via a two-step processing pathway. Primary miRNAs (pri-mir) transcribed by polymerase II or III are processed by the nuclear Drosha enzyme to give precursor-miRNAs (pre-mir), which are then exported into cytoplasm to produce mature miRNAs. Current efforts are focused on the function of miRNAs in various human diseases, as well as the identifying of new miRNAs, while little is known about how the genomic structure of miRNA genes is arranged and how the expression of miRNA genes is transcriptionally controlled by transcription factors including nuclear receptors. This project focuses on cloning miRNA genes and identifying of transcriptional regulation of miRNAs by SHP and other nuclear receptors.
Research Keywords:
Nuclear Receptors, Metabolic Syndrome, Hepatocellular Carcinoma, DNA Methylation, microRNA Gene Transcription and Function