Warrier Manya, Zhang Jun, Bura Kanwardeep, Kelley Kathryn, Wilson Martha D, Rudel Lawrence L, Brown J Mark
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
Lipids. 2016 Feb;51(2):151-7. doi: 10.1007/s11745-015-4116-7. Epub 2016 Jan 4.
Statin drugs have proven a successful and relatively safe therapy for the treatment of atherosclerotic cardiovascular disease (CVD). However, even with the substantial low-density lipoprotein (LDL) cholesterol lowering achieved with statin treatment, CVD remains the top cause of death in developed countries. Selective inhibitors of the cholesterol esterifying enzyme sterol-O acyltransferase 2 (SOAT2) hold great promise as effective CVD therapeutics. In mouse models, previous work has demonstrated that either antisense oligonucleotide (ASO) or small molecule inhibitors of SOAT2 can effectively reduce CVD progression, and even promote regression of established CVD. Although it is well known that SOAT2-driven cholesterol esterification can alter both the packaging and retention of atherogenic apoB-containing lipoproteins, here we set out to determine whether SOAT2-driven cholesterol esterification can also impact basal and liver X receptor (LXR)-stimulated fecal neutral sterol loss. These studies demonstrate that SOAT2 is a negative regulator of LXR-stimulated fecal neutral sterol loss in mice.
他汀类药物已被证明是治疗动脉粥样硬化性心血管疾病（CVD）的一种成功且相对安全的疗法。然而，即便他汀治疗能显著降低低密度脂蛋白（LDL）胆固醇水平，CVD在发达国家仍是首要死因。胆固醇酯化酶固醇-O酰基转移酶2（SOAT2）的选择性抑制剂有望成为有效的CVD治疗药物。在小鼠模型中，先前的研究表明，SOAT2的反义寡核苷酸（ASO）或小分子抑制剂均可有效减缓CVD进展，甚至促使已形成的CVD发生逆转。尽管众所周知，SOAT2驱动的胆固醇酯化可改变致动脉粥样硬化的含载脂蛋白B脂蛋白的包装和潴留，但我们在此旨在确定SOAT2驱动的胆固醇酯化是否也会影响基础状态以及肝脏X受体（LXR）刺激下的粪便中性固醇流失。这些研究表明，SOAT2是小鼠中LXR刺激下粪便中性固醇流失的负调节因子。
