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Cholesteryl Ester Transfer Protein Impairs Triglyceride Clearance via Androgen Receptor in Male Mice.
Lipids ( IF 1.9 ) Pub Date : 2020-08-11 , DOI: 10.1002/lipd.12271
Brian T Palmisano 1, 2, 3 , Uche Anozie 4 , Sophia Yu 4 , Joshua C Neuman 2 , Lin Zhu 4 , Emery M Edington 4 , Thao Luu 1, 4 , John M Stafford 1, 2, 4
Affiliation  

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.

中文翻译:

胆固醇酯转移蛋白通过雄激素受体损害雄性小鼠的甘油三酯清除率。

餐后三酰甘油(TAG)升高是心血管疾病的重要危险因素。与女性相比,男性具有更高的血浆 TAG 和受损的 TAG 清除,这可能导致心血管疾病风险的性别差异。了解 TAG 代谢中性别差异的机制可能会产生新的治疗靶点来预防心血管疾病。胆固醇酯转移蛋白 (CETP) 是一种脂质穿梭蛋白,以其对高密度脂蛋白 (HDL) 胆固醇水平的影响而闻名。尽管小鼠缺乏 CETP,但我们之前已经证明雌性小鼠中的转基因 CETP 表达会改变 TAG 代谢。然而,CETP 对雄性 TAG 代谢的影响尚不清楚。在这里,我们证明 CETP 表达增加了男性的血浆 TAG,特别是在极低密度脂蛋白 (VLDL) 中,与野生型 (WT) 雄性相比,通过削弱餐后血浆 TAG 清除率。CETP 需要性腺激素来损害 TAG 清除,这表明性激素对这种作用的作用。性腺切除术中的睾酮替代足以恢复 CETP 对 TAG 的影响。最后,CETP 需要肝脏雄激素受体 (AR) 来增加血浆 TAG。因此,男性中 CETP 的表达通过损害 TAG 清除来提高血浆 TAG通过睾酮信号传递给 AR。进一步了解 CETP 和雄激素信号如何损害 TAG 清除可能会导致减少 TAG 和降低心血管疾病风险的新方法。
更新日期:2020-08-11
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