Low‐density lipoprotein receptor is required for cholesteryl ester transfer protein to regulate triglyceride metabolism in both male and female mice

Abstract Elevated triglycerides (TGs) and impaired TG clearance increase the risk of cardiovascular disease in both men and women, but molecular mechanisms remain poorly understood. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high‐density lipoprotein cholesterol. Although mice lack CETP, transgenic expression of CETP in mice alters TG metabolism in males and females by sex‐specific mechanisms. A unifying mechanism explaining how CETP alters TG metabolism in both males and females remains unknown. Since low‐density lipoprotein receptor (LDLR) regulates both TG clearance and very low density lipoprotein (VLDL) production, LDLR may be involved in CETP‐mediated alterations in TG metabolism in both males and females. We hypothesize that LDLR is required for CETP to alter TG metabolism in both males and females. We used LDLR null mice with and without CETP to demonstrate that LDLR is required for CETP to raise plasma TGs and to impair TG clearance in males. We also demonstrate that LDLR is required for CETP to increase TG production and to increase the expression and activity of VLDL synthesis targets in response to estrogen. Additionally, we show that LDLR is required for CETP to enhance β‐oxidation. These studies support that LDLR is required for CETP to regulate TG metabolism in both males and females.