Yadong Huang, M.D., Ph.D.
Associate Investigator
Gladstone Institute of Cardiovascular Disease (GICD)
Associate Professor of Pathology and Neurology
University of California, San Francisco
Email: yhuang@gladstone.ucsf.edu
Telephone: 415-734-2000
Fax: 415-355-0824

Areas of Investigation
Research in our laboratory focuses on the biological and pathophysiological functions of apolipoprotein apoE. A long-term goal of our research is to understand the molecular and cellular mechanisms by which apoE expression level modulates very low density lipoprotein (VLDL) production and lipolysis and their related lipid metabolic disorders

Significance
Apolipoprotein (apo)E, a 299-amino acid glycoprotein with a molecular weight of 34,200 has a central role in lipid metabolism and redistribution and thus is involved in both physiological and pathophysiological processes. ApoE serves as a high-affinity ligand for several hepatic receptors, including the low density lipoprotein (LDL) receptor and the LDL receptor-related protein, and for cell-surface heparan sulfate proteoglycans (HSPG). By interacting with these receptors or with HSPG, apoE mediates the clearance of chylomicrons, VLDL, and their remnants from the circulation. Absence or structural mutations of apoE cause significant disorders in lipid metabolism, such as type III hyperlipoproteinaemia. Overexpression of apoE also cause lipid metabolic disorders by stimulating VLDL production and impairing VLDL lipolysis.

Approach
We are using cultures and transgenic mouse models to study the effects of apoE hepatocyte expression levels on VLDL metabolism at molecular and cellular levels. We are also using cell culture and mouse models to develop and evaluate novel treatment strategies for lipid metabolic disorders and the heart disease.

Contributions
ApoE serves as a ligand that mediates the clearance of VLDL and their remnants from plasma. Thus, increasing apoE levels may decrease plasma VLDL levels. However, overexpression of apoE inhibits the hydrolysis of VLDL triglycerides (VLDL-TG), leading to increased plasma triglyceride and decreased low density lipoprotein (LDL) cholesterol levels as a result of impaired lipolytic conversion of VLDL to LDL. More recently, we demonstrated that apoE stimulates hepatic VLDL production. The higher the level of apoE expressed in the liver, the greater the level of VLDL secreted from the liver. Thus, the level of apoE expression serves as an important determinant of plasma VLDL levels by altering plasma clearance, triglyceride hydrolysis, and hepatic production. Too little apoE causes type III hyperlipoproteinemia by impairing plasma clearance of triglyceride-rich lipoproteins and their remnants. Too much apoE causes hyperlipidemia by stimulating hepatic VLDL production and impairing VLDL lipolysis. Therefore, a rather narrow range of apoE levels is required to maintain normal VLDL metabolism.

Some questions addressed in ongoing studies:

• How does apoE expression level modulate VLDL production?
• How does apoE expression level modulate VLDL lipolysis?
• Does apoE overexpression cause hyperlipidemic in humans?
• Why is apoE4 a risk factor for the heart disease?

Selected References

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