Cholesteryl Ester Transfer Protein Impairs Triglyceride Clearance via Androgen Receptor in Male Mice

Abstract

Elevated postprandial triacylglycerols (TAG) are an important risk factor for cardiovascular disease. Men have higher plasma TAG and impaired TAG clearance compared to women, which may contribute to sex differences in risk of cardiovascular disease. Understanding mechanisms of sex differences in TAG metabolism may yield novel therapeutic targets to prevent cardiovascular disease. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein (HDL) cholesterol levels. Although mice lack CETP, we previously demonstrated that transgenic CETP expression in female mice alters TAG metabolism. The impact of CETP on TAG metabolism in males, however, is not well understood. Here, we demonstrate that CETP expression increases plasma TAG in males, especially in very-low density lipoprotein (VLDL), by impairing postprandial plasma TAG clearance compared to wild-type (WT) males. Gonadal hormones were required for CETP to impair TAG clearance, suggesting a role for sex hormones for this effect. Testosterone replacement in the setting of gonadectomy was sufficient to restore the effect of CETP on TAG. Lastly, liver androgen receptor (AR) was required for CETP to increase plasma TAG. Thus, expression of CETP in males raises plasma TAG by impairing TAG clearance via testosterone signaling to AR. Further understanding of how CETP and androgen signaling impair TAG clearance may lead to novel approaches to reduce TAG and mitigate risk of cardiovascular disease.

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

“…We recently demonstrated that CETP impairs postprandial TG clearance in males through liver androgen receptor signaling (Palmisano et al, 2020). Since LDLR is a major determinant of plasma TG clearance, LDLR may play a role in CETP‐mediated regulation of TG clearance.…”

“…Transgenic CETP mice were purchased from the Jackson Laboratories (C57BL/6‐Tg(CETP)UCTP20Pnu/J, Strain: 001929, Jackson Laboratories). We previously established the role of CETP on TG metabolism in both males and females relative to WT mice (Palmisano et al, 2016, 2020). LDLR deletion has been shown to impair TG clearance and increase TG production, contributing to elevated TGs relative to WT mice (Coenen et al, 2007; Ishibashi et al, 1996; Teusink et al, 2001).…”

“…We previously demonstrated that transgenic expression of cholesteryl ester transfer protein (CETP) results in increased plasma TG levels in female and male mice, but by distinct mechanisms (Palmisano et al, 2016, 2020). Mice naturally lack CETP and subsequently carry most cholesterol in HDL.…”

“…In female mice, CETP expression increased TG production in response to estrogen (Palmisano et al, 2016). In males, CETP expression impaired postprandial TG clearance (Palmisano et al, 2020). In females, CETP signals via two distinct liver networks that govern separate aspects of TG metabolism (Palmisano et al, 2016).…”

“…In females, CETP signals via two distinct liver networks that govern separate aspects of TG metabolism (Palmisano et al, 2016). In males, CETP signals through the liver androgen receptor (Palmisano et al, 2020). It remains to be determined if CETP has a common molecular target regulating TG metabolism in both males and females.…”