Major Research Areas
Researchers in the College of Graduate Studies focus their efforts where it truly matters—on the diseases and illnesses that affect many people. Much of our research activity is grouped into four areas of concentration: cancer; infectious diseases; disorders of the nervous system; and diabetes, metabolic disorders and cardiovascular diseases.
Hong Lu, PhD
- Assistant Professor of Pharmacology
Research Programs and Affiliations
- Biomedical Sciences Program
Education & Fellowships
- Fellowship: University of Kansas Medical Center, Kansas City, KS, 2006, Liver Pharmacology/Toxicology
- PhD: Rutgers University, 2002, Toxicology
- MS: Peking Union Med Coll, Beijing, China, 1997, Biochemical Pharmacology
Nuclear receptor and gene-diet interactions in Fatty liver and hyperlipidemia
Progression of fatty liver to steatohepatitis, liver cirrhosis and liver cancer
Drug metabolism and liver protection
As the metabolic center, liver is vital for the survival of the organism due to its critical role in nutrition and detoxification of xenobiotics and metabolic wastes. In modern society, a pandemic of overeating, obesity, and diabetes drives non-alcoholic fatty liver disease (NAFLD), the most common liver disease in the US. NAFLD is closely associated with hyperlipidemia, a major risk factor of cardiovascular diseases. Moreover, NAFLD can progress to more malignant liver diseases, such as non-alcoholic steatohepatitis (NASH), liver cirrhosis, and liver cancer. The major research interest of my laboratory is to understand how nuclear receptors and gene-diet interactions regulate NAFLD and the progression of fatty liver to steatohepatitis, liver cirrhosis, and liver cancer, in order to develop novel preventive and therapeutic strategies for these liver diseases.
Interaction of genetic susceptibility with environmental exposure determines the final penetrance of metabolic diseases. Many people have genetic polymorphisms/mutations that are similar to heterozygous loss of such a gene in mice. Hepatic expression of hepatocyte nuclear factor 4α (HNF4α), a master regulator of liver metabolism, is markedly decreased in diabetes, NAFLD/NASH, liver cirrhosis, and liver cancer. Overeating high-fat-high-sugar diet promotes NAFLD and hyperlipidemia. Very interestingly, we recently discovered that adult male mice with inducible liver-specific heterozygosity of HNF4α did not have an obvious phenotype when fed the low-fat chow, but rapidly developed fatty liver and hyperlipidemia after being fed a high-fat-high-sugar diet. Thus, results from studies of interactions between HNF4α heteroinsufficiency and the high-fat-high-sugar diet will have high translational power for understanding human metabolic diseases and developing novel therapeutics.
HNF4α crosstalks with diverse signaling pathways to regulate liver metabolism. Circulating glucocorticoids are altered during various psychological, metabolic, and inflammatory stresses. We found that crosstalk of HNF4α with glucocorticoid receptor (GR) may play a central role in regulating liver metabolism. We are using functional genomics approach of RNA-sequencing, ChIP-sequencing, metabolomics, and luciferase reporter assays to understand how the HNF4α-GR crosstalk regulates hepatic gene expression and metabolic function.
Glucocorticoids have potent anti-inflammatory effects and also exert anti-apoptotic, anti-fibrotic, and anti-cancer effects in liver. However, it is widely accepted that glucocorticoid excess is a key perpetrator of chronic metabolic diseases. Chronically elevated circulating GCs in extrahepatic tissues promote overeating (in brain), insulin resistance and fatty liver (in muscle), and abdominal fat stores. How to enhance/maintain the beneficial effects and avoid the side effects of glucocorticoids remains very challenging. Selective GR modulators are being developed to meet this unmet need. My laboratory is studying how these selective GR modulators affect hepatic gene expression and metabolic function. Moreover, we are developing an innovative approach of liver-specific delivery of GR modulators, to explore the therapeutic effects of liver-specific GR modulation on fatty liver diseases.