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

Nan Sheng1, Yun-qiu Wang1, Cun-fu Wang1, Meng-qi Jia1, Huan-min Niu1, Qi-qi Lu1, Ya-nan Wang1, Dan Feng2, Xiao-xue Zheng1, Hui-qing Yuan1,3
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
Correspondence to: Hui-qing Yuan:,
DOI: 10.1038/s41401-022-00909-3
Received: 6 November 2021
Accepted: 2 April 2022
Advance online: 22 April 2022


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.

Keywords: hypercholesterolemia; cholesterol biogenesis; AGR2; AKT/SREBP2; statin resistance; allicin

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