News & Research

    The Scripps Research Institute, La Jolla, California

Role of the oxysterol receptor LXR in glucose metabolism

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Integrated Physiology\Regulation of Glucose Kinetics, Signal Transduction (Non-Insulin Action)\Transcriptional Regulation, Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes

Type of Grant: Career Development

Project Start Date: January 1, 2008

Project End Date: December 31, 2012

Research Description

Cardiovascular disease accounts for more than 70% of deaths in patients with diabetes. The risk of cardiovascular mortality is four times higher in diabetes patients than in nondiabetic individuals with similar levels of serum cholesterol. Hyperglycemia appears to drive development of atherosclerosis; lesions appear earlier and with greater severity in individuals with diabetes. The details of how hyperglycemia facilitates cardiovascular disease are poorly understood. Because the majority of type 2 diabetics exhibit abnormalities in cholesterol and lipid levels, greater knowledge of the molecular mechanisms linking diabetes and atherosclerosis could have a significant impact on the health of individuals afflicted with diabetes.The liver X receptor is a protein that serves as a sensor for harmful forms of cholesterol. LXR is activated by accumulation of bad cholesterol inside cells. Once active, LXR turns on expression of genes that allow the body to dispose of detrimental cholesterol. Recently, it has been discovered that LXR can also be activated by glucose, particularly at the concentrations found in liver. When stimulated by glucose, LXR acts to decrease production of glucose in the liver and increase conversion of excess glucose to fat for storage in adipose tissue. Because this protein responds to both, glucose and cholesterol, it is possible that LXR may play a significant role connecting diabetes and atherosclerosis. Hence, study of the dual role of LXR as a cholesterol and glucose sensor may provide insight into why individuals with diabetes are at much greater risk of developing cardiovascular disease.

Reseacher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

Cardiovascular disease is the principal cause of death in patients with diabetes. Myocardial infarction, stroke, and peripheral vascular disease are more common and appear earlier in people with diabetes than in the general population. Moreover, the risk of cardiovascular mortality is 3-4 times higher in individuals with diabetes than in nondiabetic individuals with similar levels of serum cholesterol. In spite of ample epidemiological data linking hyperglycemia and cardiovascular disease, the means by which elevated glucose levels promote atherogenesis are not fully understood.

We are interested in identifying the molecular mechanisms that link diabetes and atherosclerosis. Development of atherosclerosis, the main risk factor for cardiovascular disease, is associated with abnormal levels of serum lipids and ultimately results in the formation of lipid and cholesterol deposits within the walls of blood vessels. The nuclear receptor LXR is a protein that acts as the body's sensor for excessive cholesterol accumulation. When harmful levels of cholesterol are present inside the cell, oxidized forms of cholesterol (oxysterols) are generated that bind and activate LXR. When LXR becomes active, it turns on expression of a battery of genes that prevent build up of cholesterol. We recently described that LXR activity can also be regulated by glucose. Because LXR can respond to both, cholesterol and glucose, it may represent a molecular link between diabetes and atherosclerosis. Our work aims to clarify the role of LXR as an oxysterol-glucose sensor by analyzing the genes that are regulated by LXR mutants that can respond to only one of these metabolites.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Our studies may provide insight as to why diabetics are more prone to develop atherosclerosis. By understanding how LXR activity is regulated by glucose and pathogenic forms of cholesterol, we may uncover ways to slow development of cardiovascular disease in diabetic patients. Furthermore, because there already are synthetic activators of LXR in clinical development, our work may also suggest novel ways to treat these conditions.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

Spread of the Western diet and a sedentary lifestyle has led to a spectacular increase in the incidence of obesity and its associated complications, primarily diabetes and cardiovascular disease. Particularly troubling is the fact that the incidence of these diseases has tripled in youngsters in the last 20 years in developing countries. Thus, the looming worldwide epidemic of obesity, diabetes, and cardiovascular disease represents perhaps the most significant challenge to human healthcare. I am interested in working to develop new approaches for prevention and treatment of these conditions because I want the work of my laboratory to have a significant impact on human welfare. In addition to the work sponsored by the ADA, my lab also studies other aspects of diabetes, such as its connection to obesity. As a young investigator, the ADA award provides critical funding to support the studies of my nascent lab and allows me to attract more students and postdoctoral fellows to study the pathogenesis of diabetes. More importantly, this award allows us to explore provocative avenues of research that are not likely to be funded by traditional means. It is these high-risk, high-reward projects that may have greatest impact long term.

In what direction do you see the future of diabetes research going?

Recently, there have been some large-scale efforts to find diabetes predisposing genes in human populations. These studies have described several genes that appear to drive development of diabetes in humans. Many of them are associated with beta cell physiology, but others are less well characterized. Understanding their function in normal conditions and in the context of disease will be a major area of diabetes research. The interaction of these genes with environmental influences on diabetes, such as diet and exercise, will also provide important information regarding prevention, diagnosis, and treatment of diabetes.