Department of Internal Medicine, VCU Medical Center, Richmond, VA 23298-0050, USA.
Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1795-802. doi: 10.1161/ATVBAHA.113.301634. Epub 2013 Jun 6.
Liver is the major organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or as bile acids. Intracellular hydrolysis of lipoprotein-derived cholesteryl esters (CEs) is essential to generate the free cholesterol required for this process. Earlier, we demonstrated that overexpression of human CE hydrolase (Gene symbol CES1) increased bile acid synthesis in human hepatocytes and enhanced reverse cholesterol transport in mice. The objective of the present study was to demonstrate that liver-specific deletion of its murine ortholog, Ces3, would decrease cholesterol elimination from the body and increase atherosclerosis.
Liver-specific Ces3 knockout mice (Ces3-LKO) were generated, and Ces3 deficiency did not affect the expression of genes involved in cholesterol homeostasis and free cholesterol or bile acid transport. The effects of Ces3 deficiency on the development of Western diet-induced atherosclerosis were examined in low density lipoprotein receptor knock out(-/-) mice. Despite similar plasma lipoprotein profiles, there was increased lesion development in low density lipoprotein receptor knock out(-/-)Ces3-LKO mice along with a significant decrease in the bile acid content of bile. Ces3 deficiency significantly reduced the flux of cholesterol from [(3)H]-CE-labeled high-density lipoproteins to feces (as free cholesterol and bile acids) and decreased total fecal sterol elimination.
Our results demonstrate that hepatic Ces3 modulates the hydrolysis of lipoprotein-delivered CEs and thereby regulates free cholesterol and bile acid secretion into the feces. Therefore, its deficiency results in reduced cholesterol elimination from the body, leading to significant increase in atherosclerosis. Collectively, these data establish the antiatherogenic role of hepatic CE hydrolysis.
肝脏是负责从体内排出胆固醇的主要器官，无论是通过胆汁胆固醇还是胆汁酸。脂蛋白衍生的胆固醇酯（CEs）的细胞内水解对于生成此过程所需的游离胆固醇至关重要。早期，我们证明了人胆固醇酯水解酶（基因符号 CES1）的过表达增加了人肝细胞中的胆汁酸合成，并增强了小鼠的胆固醇逆向转运。本研究的目的是证明其鼠同源物 Ces3 的肝特异性缺失会减少体内胆固醇的消除并增加动脉粥样硬化。
生成了肝特异性 Ces3 敲除小鼠（Ces3-LKO），Ces3 缺失不会影响参与胆固醇稳态和游离胆固醇或胆汁酸转运的基因的表达。在低密度脂蛋白受体敲除（-/-）小鼠中检查了 Ces3 缺失对西方饮食诱导的动脉粥样硬化发展的影响。尽管血浆脂蛋白谱相似，但在低密度脂蛋白受体敲除（-/-）Ces3-LKO 小鼠中病变发展增加，同时胆汁中的胆汁酸含量显着降低。Ces3 缺失显着减少了从 [(3)H]-CE 标记的高密度脂蛋白到粪便（作为游离胆固醇和胆汁酸）的胆固醇通量，并减少了总粪便固醇的消除。
我们的结果表明，肝 Ces3 调节脂蛋白传递的 CEs 的水解，从而调节游离胆固醇和胆汁酸分泌到粪便中。因此，其缺乏导致体内胆固醇消除减少，导致动脉粥样硬化显着增加。总之，这些数据确立了肝 CE 水解的抗动脉粥样硬化作用。
