Abstract
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.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81872896, 82173839 and 32000891), and Natural Science Foundation of Shandong Province (ZR2020QH363).
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NS and YQW performed the experiments, analyzed and interpreted the results, and wrote the paper. CFW collected clinical samples. MQJ and HMN analyzed and interpreted the results. QQL, YNW and XXZ assisted in animal experiments. DF was involved in data analysis. HQY designed the research, analyzed and interpreted the results, and wrote the paper. All authors read and approved the final paper.
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Sheng, N., Wang, Yq., Wang, Cf. et al. AGR2-induced cholesterol synthesis drives lovastatin resistance that is overcome by combination therapy with allicin. Acta Pharmacol Sin 43, 2905–2916 (2022). https://doi.org/10.1038/s41401-022-00909-3
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DOI: https://doi.org/10.1038/s41401-022-00909-3
