AGR2-induced cholesterol synthesis drives lovastatin resistance that is overcome by combination therapy with allicin.
AGR2-induced cholesterol synthesis drives lovastatin resistance that is overcome by combination therapy with allicin.
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AGR2 诱导的胆固醇合成会导致洛伐他汀耐药，可通过与大蒜素联合治疗来克服。
DOI：
10.1038/s41401-022-00909-3
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Hui-Qing Yuan
中科院分区：
文献类型：
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作者：
Nan Sheng;Yun-Qiu Wang;Cun-Fu Wang;Meng-Qi Jia;Huan-Min Niu;Qi-Qi Lu;Ya-Nan Wang;Dan Feng;Xiao-Xue Zheng;Hui-Qing Yuan
前梯度2（AGR2）是一种蛋白质二硫键异构酶（PDI），是生理和病理条件下的多功能蛋白质。在这项研究中，我们研究了 AGR2 在调节胆固醇生物合成、洛伐他汀降脂效率以及预防高胆固醇血症/他汀类药物引起的肝损伤中的作用。我们发现，与喂养正常饲料（NCD）或高脂饮食（HFD）的野生型同窝小鼠的水平相比，AGR2敲除显着降低了全身或肝细胞特异性Agr2缺失突变体小鼠的肝脏和血清总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）。相比之下，AGR2 过度表达 (Agr2/Tg) 的小鼠则表现出胆固醇水平升高。机制研究表明，AGR2 在某种程度上以 PDI 基序依赖性方式通过激活 AKT/甾醇调节元件结合蛋白 2 (SREBP2) 影响胆固醇的生物合成。此外，AGR2升高导致洛伐他汀（10 mg· kg−1· d−1，腹腔注射，持续2周）对高胆固醇血症（hyperCho）小鼠的降脂功效显着下降，这一点通过他汀类药物治疗患者的临床样本结果得到验证。我们发现洛伐他汀对 AGR2 表达的影响有限，但 AGR2 在喂食 HFD 的 Agr2/Tg 小鼠中是可诱导的。进一步的研究表明，在高胆固醇血症Agr2/Tg小鼠中，药物引起的肝毒性和炎症反应得到减轻，这表明AGR2在脂质管理和hyperCho/他汀类药物引起的肝损伤中具有双重功能。重要的是，洛伐他汀的 AGR2 降低降脂功效通过同时给予巯基反应性化合物大蒜素（20mg·kg−1·d−1，腹腔注射，持续 2 周）而至少部分减弱。这些结果证明了AGR2在胆固醇代谢、耐药性和肝脏保护中的新作用，表明AGR2可以作为临床降脂药物选择的潜在预测因子。
Anterior gradient 2 (AGR2), a protein disulfide isomerase (PDI), is a multifunctional protein under physiological and pathological conditions. In this study we investigated the roles of AGR2 in regulating cholesterol biogenesis, lipid-lowering efficiency of lovastatin as well as in protection against hypercholesterolemia/statin-induced liver injury. We showed that AGR2 knockout significantly decreased hepatic and serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in mice with whole-body or hepatocyte-specificAgr2-null mutant, compared with the levels in their wild-type littermates fed a normal chow diet (NCD) or high-fat diet (HFD). In contrast, mice with AGR2 overexpression (Agr2/Tg) exhibited an increased cholesterol level. Mechanistic studies revealed that AGR2 affected cholesterol biogenesisviaactivation of AKT/sterol regulatory element-binding protein-2 (SREBP2), to some extent, in a PDI motif-dependent manner. Moreover, elevated AGR2 led to a significant decrease in the lipid-lowering efficacy of lovastatin (10 mg· kg−1· d−1, ip, for 2 weeks) in mice with hypercholesterolemia (hyperCho), which was validated by results obtained from clinical samples in statin-treated patients. We showed that lovastatin had limited effect on AGR2 expression, but AGR2 was inducible inAgr2/Tg mice fed a HFD. Further investigations demonstrated that drug-induced liver toxicity and inflammatory reactions were alleviated in hypercholesterolemicAgr2/Tg mice, suggesting the dual functions of AGR2 in lipid management and hyperCho/statin-induced liver injury. Importantly, the AGR2-reduced lipid-lowering efficacy of lovastatin was attenuated, at least partially, by co-administration of a sulfhydryl-reactive compound allicin (20 mg· kg−1· d−1, ip, for 2 weeks). These results demonstrate a novel role of AGR2 in cholesterol metabolism, drug resistance and liver protection, suggesting AGR2 as a potential predictor for selection of lipid-lowering drugs in clinic.