Abstract 1660: Short-term Overexpression of CD36 in the Liver Augments Hepatic Lipid Storage and VLDL-triglyceride Secretion: Implications for Diet-Induced Obesity and Type 2 Diabetes
Type 2 diabetes (T2D) is associated with a high risk of cardiovascular disease. The management of dyslipidemia in T2D is one element in the multifactorial approach to prevent coronary heart disease. Since the levels of plasma fatty acids (FA), triglycerides (TG) and lipoproteins are primarily controlled by the liver it is likely that aberrant hepatic FA uptake and handling contributes to the development of T2D. One protein identified as being central in FA transport is CD36. We have recently shown that in the heart, CD36-regulated FA uptake controls 50 – 80% of FA utilization. In livers of healthy lean animals, CD36 is expressed at extremely low levels and is not believed to play a significant role in the uptake and metabolism of FA. However, we recently obtained evidence that CD36 mRNA and protein expression in the mouse liver are significantly (p<0.001) increased at 5 weeks after the initiation of a diet rich in FA (60% kcal from lard versus 10% kcal from lard). To investigate whether elevated hepatic CD36 expression alone is sufficient to contribute to the pathogenesis of lipid abnormalities associated with diet-induced obesity, we performed in vivo gene delivery of a recombinant adenovirus harboring CD36 cDNA (Ad.CD36) into lean mice. In these mice, seven days following systemic injection of Ad.CD36, TG storage in the liver was increased 2-fold (p<0.01) compared to mice administered a control adenovirus (Ad.Null). Furthermore, plasma TG were increased 1.5-fold (p<0.05) in the Ad.CD36-injected mice compared to Ad.Null-injected mice, which was associated with an increase in VLDL-TG secretion. These data suggest that elevated plasma FA levels can increase the expression of CD36 in the mouse liver and reveal an important role for CD36 in hepatic lipid storage and secretion. Our data also show that high CD36 expression alone is sufficient to recapitulate the alterations in liver lipid storage and VLDL-TG secretion observed in mice fed a high-fat diet. Together our data suggest that alterations in CD36 expression accelerate the development of T2D diabetes and may prove to be a novel target for liver specific pharmacological inhibition for the treatment of T2D.