AGR2-induced cholesterol synthesis drives lovastatin resistance that is overcome by combination therapy with allicin  

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 

机构地区：[1]Key Laboratory of Experimental Teratology of Ministry of Education,Institute of Medical Sciences/Department of Neurology,The Second Hospital,Cheeloo College of Medicine,Shandong University,Ji-nan 250021,China [2]Department of Natural Medicinal Chemistry and Pharmacognosy,School of Pharmacy,Qingdao University,Qingdao 266021,China [3]Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Cheeloo College of Medicine,Shandong University,Ji-nan 250012,China

出　　处：《Acta Pharmacologica Sinica》2022年第11期2905-2916,共12页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(81872896,82173839 and 32000891);Natural Science Foundation of Shandong Province(ZR2020QH363).

摘　　要：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-specific Agr2-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 biogenesis via activation 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 in Agr2/Tg mice fed a HFD.Further investigations demonstrated that drug-induced liver toxicity and inflammatory reactions were alleviated in hypercholesterolemic Agr2/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.

关 键 词：HYPERCHOLESTEROLEMIA cholesterol biogenesis AGR2 AKT/SREBP2 statin resistance ALLICIN 

分 类 号：R96[医药卫生—药理学]