As researchers identify the links between the fatty acid transport system and conditions such as insulin resistance, type 2 diabetes, and heart failure, they have identified a pathway, endothelial CD36, that may play a key role. Blocking this pathway could prevent destructive lipid accumulation and improve insulin sensitivity.

CD36: A Multifunctional Metabolic Protein

Circulating fatty acids must transfer across the endothelial cell barrier to get from blood to tissues. The molecular events behind this process are not yet known. Several proteins have been implicated in both the uptake and the accumulation of fatty acids in tissue and organs, including a scavenger protein called cluster of differentiation 36, or CD36, first linked to lipid metabolism 25 years ago.

Since then, the protein has proved to play important and diverse immuno-metabolic roles, from the activation of peroxisome proliferator-activated receptors (PPARs) to lipid accumulation, inflammation, and generation of arterial foam cells. In collaboration with researchers at Washington University in St. Louis, NYU Langone investigators studied its role in lipid transport across the endothelium of blood vessels.

Research Uncovers a Key Fat Transporter

In this latest study of CD36, Ira J. Goldberg, MD, the Clarissa and Edgar Bronfman, Jr. Professor of Endocrinology and director of the Division of Endocrinology, Diabetes, and Metabolism, investigated the distribution of CD36 receptors on endothelial cells and cardiomyocytes in both mouse and human heart tissue. Then, using mouse models, his team sought to determine whether fatty acid uptake into muscle, organs, and other tissue depends on endothelial CD36, CD36 found on parenchymal cells like cardiomyocytes, or both.

Dr. Goldberg and his team showed that endothelial cells robustly express CD36 in small blood vessels of human and mouse hearts. Cardiomyocytes also express this protein. Deleting CD36 in either type of cell in mice reduced the lipid accumulation that normally occurs in the heart during fasting. However, there were significant differences between the functions of CD36 in endothelial cells and in cardiomyocytes.

“We discovered that if you knock out only the endothelial CD36, there is a defect in fat uptake by the heart, skeletal muscles, and brown adipose tissue,” says Dr. Goldberg. The same was not seen in cardiomyocyte CD36–deficient mice, a crucial difference, suggesting that only endothelial CD36 is necessary to move fatty acids from the blood into the heart and other tissues.

“We discovered that if you knock out only the endothelial CD36, there is a defect in fat uptake by the heart, skeletal muscles, and brown adipose tissue.”—Ira J. Goldberg, MD, Director of the Division of Endocrinology, Diabetes, and Metabolism

“On top of that, the endothelial CD36–deficient mice that were fed high-fat diets showed improved glucose tolerance and became more insulin sensitive, presumably because they had less fat in the muscle,” says Dr. Goldberg.

Moreover, expression of several genes in the heart that modulate glucose metabolism and insulin action increased in the endothelial CD36–deficient mice but decreased in the cardiomyocyte CD36–deficient mice. “We are now trying to better understand the relationship between the movement of fat across endothelial cells and into tissues, and in turn how it affects insulin signaling and diabetes,” says Dr. Goldberg.

Targeting CD36 for Treatment

The ultimate goal, notes Dr. Goldberg, is to refine this process—perhaps directly targeting endothelial CD36 to block lipid uptake into tissues—to make insulin work better and treat diabetes. “We want to know whether it can be a therapy for other diseases as well, such as heart failure associated with too much fat uptake into the heart,” says Dr. Goldberg. In an upcoming study, his team will test whether one form of heart disease can actually be cured in mice by targeting this transport system.