Cholesteryl Ester Transfer Protein Modulates Liver Sex Hormone Signaling to Alter Triglyceride Metabolism in Male and Female Transgenic Mice

Abstract

Elevated plasma triglycerides (TGs) increase risk of cardiovascular disease, especially in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here, I explore the role of Cholesteryl Ester Transfer Protein (CETP) in the regulation of TG metabolism in mice, which naturally lack CETP. I found that transgenic expression of CETP disrupts sex hormone signaling in both males and females to alter liver and plasma TG metabolism. In females, estrogen treatment increased plasma TGs by increasing production of Very-Low Density Lipoprotein (VLDL) in a pathway dependent on liver expression of Small Heterodimer Partner (SHP). Additionally, CETP expression increased liver beta-oxidation and reduced liver TG content in a pathway dependent on liver expression of Estrogen Receptor alpha (ER alpha). In males, CETP expression raised plasma TGs, but by a different mechanism than in females. CETP expression impaired TG clearance by reducing liver Low Density Lipoprotein Receptor (LDLR) expression in a pathway dependent on male sex hormones. In both males and females, LDLR expression was required for CETP to alter TG metabolism. Thus, LDLR is a major upstream determinant of the ability of CETP to alter TG metabolism in both males and females. This work has identified that CETP alters the sex hormone regulation of a number of pathways involved in TG metabolism in both males and females. Further understanding of the role of CETP in TG metabolism in males and females may lead to discovery of novel pathways that contribute to risk of cardiovascular disease.