Adipose tissue specific CETP expression in mice: impact on lipoprotein metabolism

Hongwen Zhou, Zhiqiang Li, Mohamad R. Hojjati, David Jang, Thomas P. Beyer, Guoqing Cao, Alan R. Tall, and Xian-Cheng Jiang

Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203

Corresponding Author: xjiang{at}downstate.edu

Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that mediates the transfer and exchange of CE and triglyceride between plasma lipoproteins, and plays an important role in HDL metabolism. Adipose tissue appears to be a highly conserved site of CETP expression across species. However, the function of CETP in adipose tissue is poorly understood. To investigate the impact of adipose CETP expression on lipid metabolism, we created adipose tissue specific CETP transgenic (CETPTg) mice, using the aP2 promoter to drive a CETP minigene. We established two lines of transgenic animals. CETP mRNA is predominantly expressed in adipose tissue in both lines. There are low levels of expression in heart, muscle and lung, but there is no expression in other tissues, including the liver and peritoneal macrophages. Plasma CETP mass and activity are readily detectable in both lines of mice, but not in wild type (WT) mice. Plasma lipoprotein analysis shows marked reductions in HDL cholesterol and phospholipids and increases of non-HDL lipids, decreased apoA-I and increased apoB48 and apoB100. Unexpectedly, CETPTg adipocytes are significantly smaller than those in WT mice (44%), triglyceride and cholesterol in adipose tissue were significantly decreased compared to WT mice (50% and 37%, respectively), while phospholipids showed no significant changes. To study the mechanism, we measured PPAR, SREBP-1c, lipoprotein lipase (LPL), and hormonal sensitive lipase (HSL) in aP2-CETPTg adipose tissue and WT controls. We found that PPAR, SREBP-1c, and LPL mRNA levels are significantly decreased in the transgenic mice compared with controls (26%, 33%, and 22%), while HSL showed no significant change. In conclusion, adipose tissue CETP makes a major contribution to CETP in the circulation, reduces HDL and increases non-HDL cholesterol levels. Moreover, adipose tissue CETP expression changes triglyceride and cholesterol content and size of adipocytes.

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