News & Research

    Boston University School of Medicine, Boston, Massachusetts

How CD36 and Caveolin-1 affect fatty acid uptake

General Research Subject: Type 2 Diabetes

Focus: Adipocytes, Insulin Action\Insulin Resistance, Integrated Physiology\Fatty Acid Metabolism

Type of Grant: Basic Science

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Diabetes Type: Type 2 diabetes

Research Description

This project addresses the important health issues of type 2 diabetes and obesity, public health challenges for which therapies are inadequate.  Diabetes and obesity have already been recognized as a national crisis, and are soon to be an international health crisis. While the adverse effects of high blood sugar have long been recognized, adverse effects of high levels of fat, in the form of triglycerides in particles that circulate in the blood (lipoproteins) and in the form of fatty acids (FA) are now recognized. FA are essential nutrients for humans, but when not handled properly by cells they are present at high levels in blood plasma and in cells. As normal fat depots become overstuffed with fat, excess fat is stored in many organs in the body, including the heart and the liver.

Fat stores then secrete toxins, which include FA acids, into the organs and the blood. Our studies investigate how two membrane proteins influence the movement of FA in membranes and their metabolism inside a cell. We use a multidisciplinary approach, combining methods of physics, biochemistry, and molecular biology. Our work recognizes the distinctly different properties of the FA molecule compared with the glucose molecule. We apply unique strategies to understand how FA are handled in the cell plasma membrane, the barrier between the live cell and the constituents of the blood plasma, and how they are stored in cells. The outcomes will help design new therapies for the diabetes and obesity.

Research Profile

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

Obesity, glucose intolerance, and diabetes can all be considered not as distinct disease states, but part of a broader disorder, metabolic syndrome, which encompasses abnormal transport and metabolism of both glucose and fatty acid (FA).

A key step in transport is the passage of these life-sustaining nutrients across the membrane surrounding a cell, the plasma membrane. While glucose requires a specialized type of protein to allow its passage through the membrane barrier FA can pass through freely.  Yet there are proteins located in the plasma membrane that seem to influence the accumulation of FA in cells, including the fat cell which overstores FA in metabolic syndrome. However, it remains poorly understood whether these proteins regulate FA uptake by affecting their transmembrane movement or intracellular metabolism.

This proposal presents a unique project to shed new light on the functions of two such proteins: one which is located mainly on the outside layer of the cell membrane (CD36) and one that is located on the inner leaflet of the cell membrane (Caveolin-1). We will use newly developed methods to watch FA arrive in the outer membrane and pass through to the inside of the, and measure how the FA are metabolized in cells with different amounts of each of the proteins, and the two proteins in combination, are added to the cell by 'expression' through genetic manipulations

Our work aims to give a better understanding of the individual role of CD36 or Caveolin-1 as well as their synergistic effects in the regulation of FA transport and to decipher their links to metabolism. The details have to be meticulously unraveled in fine detail because both proteins have several other functions. Our approaches will aid in designing new therapies for the treatment of type II diabetes and obesity using these two proteins as potential targets without disturbing other vital functions. Functions. functions. This has to be done very carefully, thus a drug designed to affect FA handling in a way favorable to controlling the diabetic state could have multiple undesired side effects if not meticulously designed to be specific. 

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

The control and management of type 2 diabetes and obesity in humans is fraught with complexities and difficulties and is often dealt with primarily at psychological levels. Although many factors can contribute to these diseases, basic scientific principles of physics, biochemistry and physiology still underlie the development and manifestations of type 2 diabetes and obesity. 

I am excited because our work will approach the problem at a fundamental scientific level without behavioral bias. Scientists study issues in a controlled manner, and as a result will find fundamental rules that will apply to most persons with diabetes. One might ask then why the results and the answers at the basic level have not yet been found, and the reason is that it is more complex that first imagined. The involvement of fatty acids as well as glucose is a prime illustration. And the ways that fatty acids affect diabetes are complex and not well enough understood.

Beyond that, I am also excited because in the recent focus on fatty acids and fat storage, new methods have been developed that will allow  more definitive experiments to be designed and performed.  Our own lab has recently found ways to follow the movement of fatty acids across membranes in a step by step way, and to study this transport process and the fate of fatty acids (metabolism) in cells. We can now look closely at key proteins in the plasma membranes of cells to pinpoint their roles and activities in diabetes.

My contributions consist of finding more of the fundamental rules of our human physiology that relate to diabetes and  understanding some specific mechanisms well enough to design new pharmaceutical therapies. Since the proteins that we are studying seem to play roles in accumulating fat in cells, we may be able to gain some control to influence cells to store the right amount of fat needed for energy but not to accumulate to a level that has detrimental effects.

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

I began my research career with studies of plasma lipoproteins by a then novel method, NMR spectroscopy. The low density lipoprotein LDL, which carries most of the cholesterol in blood, and was known to be a direct link to atherosclerosis by transporting cholesterol into the vessel wall. My enthusiasm in 'translation' of basic research in lipoproteins stimulated me to apply new methods to atherosclerotic plaques. Accumulating evidence have shown that people with type 2 diabetes are in greater chance of developing atherosclerosis, which make deciphering the mechanism and finding treatment of type 2 diabetes an urgent issue.

My overall research design to study diabetes includes two different but intrinsically related strategies. One of them is focusing on fat storage in and around organs in obese patients often with co-existing diabetic syndrome by using MRI. Supported by the clinical data from these case studies, this project focuses on the function of two key proteins in fatty acid transport and metabolism to uncover the mechanism of diabetes at the molecular level. Our research efforts from this aspect build the bridge directly to successful designing of effective drug therapies.

Overall, I feel greatly privileged to have reached a point in my career where I can contribute to the research at a variety of levels. This award tremendously encouraged me to continue on this very challenging but promising road.

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

I will continue work at both basic and applied levels, since the work that is planned will involve extensive work.

In addition, our laboratory is leading a multi-disciplinary project on obese type 2 diabetics.   These studies provided a unique platform that allows efficient communication between clinical and molecular and cellular biological aspects under the same research environment.

The study performs MRI to calculate the amount of fat around vital organs, such as the heart, and this fat can accumulate to a volume where it has undesired effects on heart functions. We are investigating whether loss of general body fat is accompanied by loss around the heart and organs. We have found already that some obese persons have low amounts of heart and organ fat at the beginning of the study, with better functioning organs, This clearly shows that not all type 2 diabetes can be put into the same category, and that a close look at the internal anatomy is valuable in evaluation the manifestations of type 2 diabetes.

In our newest studies we have begun to image a few patients who are undergoing bariatric surgery.  We have found that after one year, most of these subjects have also lost significant amounts of fat around the heart.  I look forward to continuing work in this area and finding how much organ functions improve after this localized fat loss and how useful MRI might be in the future health of these individuals. I believe that diabetes research   welcoming an era predominated by multi-disciplinary projects which will promote a variety of successful therapies.