Pessin, Jeffrey E, PhD
Molecular mechanisms regulating nuclear SREBP-1c stability and lipogenesis
General Research Subject: Type 2 Diabetes
Focus: Diabetic Dyslipidemia, Insulin Action, Insulin Action\Metabolism, Integrated Physiology, Integrated Physiology\Liver
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
The dysregulation of lipid metabolism is a major risk factor for type 2 diabetes, obesity and cardiovascular diseases, which constitute the leading cause of death in US. Approximately nearly 25 million people in US have diabetes, and strikingly, 70% of these patients also have non-alcoholic fatty liver disease (NAFLD). Previous studies have demonstrated that the SREBP1c transcription factor is a key lipogenic activator in hepatocytes that is regulated at multiple levels, including transcription, proteolytic maturation from its precursor, and nuclear protein stability. Under normal physiological conditions, insulin activates SREBP-1c by stimulating all these regulatory steps. For example, recent studies have shown that mTORC1-dependent phosphorylation of lipin results in the transcriptional activation of SREBP-1 expression. Insulin regulation of SREBP-1c has primarily focused on SREBP-1c transcription and maturation, however the molecular mechanisms of how insulin regulates nuclear SREBP-1c and the dysregulation of nuclear SREBP-1c in states of insulin resistance remain poorly understood. We have demonstrated that CDK8 is a novel regulator of de novo lipogenesis by phosphorylating nuclear SREBP-1c and in turn promoting degradation of this transcription factor.
Importantly, we also found that food intake in vivo causes a rapid loss of the CDK8/CycC protein complex through a mTORC1 dependent signaling pathway. Thus, this application is highly significant because we propose to study a novel component of insulin signaling in the control of de novo lipogenesis that is further highlighted by a recent genome-wide linkage study showing that CDK8 is one of the candidate genes implicated in type 2 diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
It is well-known that dysregulation of lipid homeostasis is a risk factor for major human diseases, including Type 2 Diabetes, obesity and cardiovascular diseases, which constitute the leading cause of death in US. According to the CDC data, nearly 24 million people in US had diabetes in 2007, and strikingly, up to 70% of those diabetic patients were also diagnosed with non-alcoholic fatty liver disease (NAFLD), which is tightly associated with hepatic insulin resistance. The most common feature of NAFLD is excessive fat accumulation in hepatocytes primarily due to increased triglyceride synthesis. Although lipolysis of peripheral fat and dietary fatty acids can supply free fatty acids for hepatic triglyceride synthesis, about 30% of hepatic fatty acids are from de novo lipogenesis in NAFLD, while the normal contribution is 3-5%. Moreover, increased hepatic lipogenesis also leads to insulin resistance, dyslipidemia and atherosclerosis, the primary risk factors for heart disease, which is the number one cause of mortality in diabetic patients. Therefore, understanding the regulation of hepatic de novo lipogenesis is highly important and clearly relevant to insulin resistance and diabetes.
Previous studies have demonstrated that the SREBP-1c transcription factor is a key lipogenic activator in hepatocytes, as it can stimulate the transcription of a series of rate-limiting enzymes in the pathway of fatty acid as well as triglyceride biosynthesis. Understanding the normal and pathophysiologic regulation of the SREBP-1c transcriptional activity will improve our understanding of how hepatic de novo lipogenesis is controlled. In this regard, we have recently demonstrated that the CDK8/CycC complex plays an important role in the regulation of nuclear SREBP-1c stability and therefore SREBP-1c dependent lipogenic gene transcription. The current proposal is directed at understanding the molecular mechanisms regulating CDK8/CycC function and its dysregulation in states of insulin resistance, Type 2 Diabetes and NAFLD.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Type 2 Diabetes Mellitus is a complex heterogenous disease process that results from the interplay of multiple genetic factors that are influenced by numerous environmental factors. Thus, development of effective treatments and/or a cure requires that we understand the molecular basis for the interaction of these various factors. Over the past several years we have made tremendous strides in this direction but obviously there is a lot more that needs to be understood.
Our project is focused on an important and critical aspect of diabetes, which is the high rate of liver lipid synthesis and accumulation. Abnormal lipid levels results in obesity and the accumulation of lipids in skeletal muscle and the liver, and is common to almost all Type 2 Diabetic individuals. Through several known mechanisms inappropriate intratissue lipids induces insulin resistance, the hallmark of Type 2 Diabetes. Moreover, lipid accumulation in the brain blocks normal nutrient sensing and in the pancreas alters glucose-stimulated insulin secretion.
The abnormal lipids accumulation result from a variety of factors but one key mechanism is dysregulated liver lipogenesis. In normal individuals, liver synthesizes fatty acids (de novo lipogenesis) in the fed state and suppresses fatty acid synthesis in the fasted state. However, in diabetic individuals the liver continuously synthesizes fatty acids in both the fed and fasted state. The reason for the inability of fasting to block fatty acid synthesis accounts for the majority of dyslipidemia in diabetes. Our project has uncovered a novel pathway that controls de novo lipogenesis and we have found that this pathway is dysfunctional in diabetic animal models. The goal of this project is carefully dissect this new pathway at a molecular level such that we can then devise normal interventions to restore normal liver regulation of fatty acid synthesis.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I personally became interested in diabetes in the 1980’s for several reasons. First, my father and wife’s cousin had type II and type I diabetes, respectively and this had a major impact in their health and importantly, their quality of life. Moreover, this disease affects an enormous number of individuals throughout the world. In addition to the negative health issues, there is also a large financial burden on individuals and families.
Since my early training, I have continuous worked on understanding the normal and pathophysiology mechanisms responsible for insulin resistance and diabetes. In 2008 I became the director of the Einstein Diabetes Research Center and have been continually exposed to the health impact both from several family members and friends who have developed diabetes and subsequent diabetic complications, as well as from the large number of patients treated in our diabetes clinics. The burden both financially and more importantly reduced quality and extent of life can not be ignored and it is imperative that we develop improvement treatment modalities.
In what direction do you see the future of diabetes research going?
There are several approaches that diabetes research needs to take in order to make in-roads to this complex metabolic disease process. First, for Type I diabetes further development of an accurate and continuous glucose sensing system coupled with an artificial insulin/glucagon delivery system will provide a more safe and effective treatment until a biological solution can be develop. In this regard, it is unlikely that transplant technology and/or stem cell differentiation into beta cells will be an effective approach in the conceivable future. However, blocking immunological attack and/or generating immune tolerance are becoming more and more likely in the next period of time. This will not cure current Type 1 Diabetic individuals but will provide an effective means to prevent the development of new Type I Diabetic patients.
In the case of Type 2 Diabetes, the single greatest improvement is not to prevent insulin resistance per se but to decrease the global obesity epidemic that in turn is driving the Type 2 Diabetes epidemic. Obesity research is focusing on several different areas but the most likely will be to development therapies that will reduce caloric intake and restore normal hypothalamic nutrient sensing. As there are currently many obstacles in developing medical therapies to limit food intake, gastric bypass remains a viable alternative, at least for those diabetic individuals that are morbidly obese.
Alternatively, other more currently tractable approaches are to limit the insulin resistance through improvement of metabolic profile. As such, this proposal is aimed at reducing hepatic lipogenesis that will improve liver function and decrease adiposity and ectopic lipid accumulation. By enhancing insulin sensitivity through reduction in lipid burden will go a long way to improve the overall health and quality of life for the majority of diabetic and obese individuals.
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