Lin, Jiandie , PhD
Regulation of hepatic lipid metabolism through the pgc-1alpha/smarcd1 coactivator complex
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology\Fatty Acid Metabolism
Type of Grant: Career Development
Project Start Date: July 1, 2008
Project End Date: June 30, 2013
Metabolic syndrome is emerging as a worldwide epidemic that becomes a major medical and social problem. Patients with this syndrome typically are obese, have high blood glucose, and develop abnormal blood lipid profiles. As a result, they have higher risk for type 2 diabetes and cardiovascular diseases. An important feature of these metabolic derangements is that the body fails to properly respond to insulin, a pancreatic hormone that controls the activity of many metabolic pathways. Despite the importance of insulin resistance in metabolic syndrome, it is not at all clear how this occurs. Several recent discoveries have shown that the accumulation of lipids in tissues that are not supposed to store fats, for example in the liver and skeletal muscle, is associated with insulin resistance.
So it seems likely that abnormal lipid metabolism is a potential cause of insulin resistance. The goals of the proposed studies are to understand how normal lipid balance is regulated, in particular the mechanisms that control fat burning, and to determine the significance of these regulatory factors in the healthy and disease states. These studies will shed light on new pathways that control metabolism, and more importantly, uncover novel therapeutic targets for the treatment of type 2 diabetes and associated lipid disorders.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our laboratory is investigating the molecular pathways that control the balance of nutrient storage and utilization in the body. We are particularly interested in dissecting pathogenic changes that contribute to the development of metabolic disorders, such as obesity, type 2 diabetes, and hyperlipidemia. The overall goal of this project is to understand how the program of fat oxidation is regulated in the liver under normal and disease states. It has been appreciated that fatty liver, characterized by excess fat accumulation in the liver, is commonly associated with metabolic syndrome and type 2 diabetes. Fatty liver is an early event in the development of non-alcoholic fatty liver disease, which significantly increases the risk for liver damages, inflammation, and the formation of scar tissues.
In severe cases, liver cirrhosis ensures and the only effective treatment is liver transplantation. Fatty liver is also found to occur more frequently in the insulin-resistant state. Remarkably, lowering fat levels in the liver can improve insulin sensitivity in animal models. In this study, we attempt to address the molecular circuitry that controls hepatic lipid oxidation and how it impacts the balance of lipid storage in this organ. We hope that by dissecting the molecules that control fat oxidation, we will uncover new targets for future therapeutic development. These studies have the potential to impact the treatments of non-alcoholic fatty liver disease as well as type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
It is clear that the therapeutic options currently available for diabetes are inadequate to cure the complex metabolic derangements of this disease. Many treatments have severe side effects and/or toxicity profile that could pose an increased risk for patients over a prolonged period. However, our ability to develop new drugs for these unmet medical needs is hampered by the poor understanding of the underlying biology and pathology associated with diabetes. Basic medical research, as our proposed studies here, is critical to enhance our knowledge about the disease and provide an opportunity to find new cures. Specifically, this project will help shed light on the fundamental biology of lipid metabolism in the liver, a central hub for metabolic control, and also provide novel molecular targets for potential therapeutic development.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I engage in diabetes research not only because I am intrigued by the complexity of this metabolic disorder, but also because the progress made in this area will undoubtedly have major impact on human health. Understanding the complex crosstalk among tissues and molecular pathways is a great challenge and a fertile ground for new and exciting discoveries. This award is important for me to transition into an independent research scientist and it is critical for the development of a robust research program in my laboratory to tackle important questions in diabetes research.
In what direction do you see the future of diabetes research going?
The future of diabetes research will benefit enormously from interdisciplinary efforts and the emerging of new technologies for biomedical research. More sophisticated understanding of biology and physiology will certainly emerge from these new experimental approaches. As a result, we will be able to decipher the disease mechanisms and discover target pathways for drug development. In addition, the prominence of metabolic syndrome in our society draws a great deal of attention from the young generation of scientists and trainees. The expansion of the talent pool will also positively impact future diabetes research.
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