Theranostics 2022; 12(5):2351-2369. doi:10.7150/thno.70692 This issue Cite

Research Paper

SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation

Wonseok Lee, Hyun Young Kim, You-Jin Choi, Seung-Hwan Jung, Yoon Ah Nam, Yunfan Zhang, Sung Ho Yun, Tong-Shin Chang, Byung-Hoon Lee

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

Citation:
Lee W, Kim HY, Choi YJ, Jung SH, Nam YA, Zhang Y, Yun SH, Chang TS, Lee BH. SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation. Theranostics 2022; 12(5):2351-2369. doi:10.7150/thno.70692. https://www.thno.org/v12p2351.htm
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Abstract

Graphic abstract

Rationale: While some non-steroidal anti-inflammatory drugs (NSAIDs) are reported to induce hepatic steatosis, the molecular mechanisms are poorly understood. This study presented the mechanism by which NSAIDs induce hepatic lipid accumulation.

Methods: Mouse primary hepatocytes and HepG2 cells were used to examine the underlying mechanism of NSAID-induced hepatic steatosis. Lipid accumulation was measured using Nile-red assay and BODIPY 493/503. The activity of chaperone-mediated autophagy (CMA) was determined by western blotting, qRT-PCR, and confocal imaging. The effect of NSAID on CMA inhibition was evaluated in vivo using diclofenac and CMA activator (AR7) administered mice.

Results: All tested NSAIDs in this study accumulated neutral lipids in hepatocytes, diclofenac having demonstrated the most potency in that regard. Diclofenac-induced lipid accumulation was confirmed in both mouse primary hepatocytes and the liver of mice. NSAIDs inhibited CMA, as reflected by the decreased expression of lysosome-associated membrane glycoprotein 2 isoform A (LAMP2A) protein, the increased expression of CMA substrate proteins such as PLIN2, and the decreased activity of photoactivatable KFERQ-PAmCherry reporter. Reactivation of CMA by treatment with AR7 or overexpression of LAMP2A inhibited diclofenac-induced lipid accumulation and hepatotoxicity. Upregulation of sorting nexin 10 (SNX10) via the CHOP-dependent endoplasmic reticulum stress response and thus maturation of cathepsin A (CTSA) was shown to be responsible for the lysosomal degradation of LAMP2A by diclofenac.

Conclusion: We demonstrated that NSAIDs induced SNX10- and CTSA-dependent degradation of LAMP2A, thereby leading to the suppression of CMA. In turn, impaired CMA failed to degrade PLIN2 and disrupted cellular lipid homeostasis, thus leading to NSAID-induced steatosis and hepatotoxicity.

Keywords: Chaperone-mediated autophagy, Diclofenac, NSAIDs, Perilipin 2, Sorting nexin 10


Citation styles

APA
Lee, W., Kim, H.Y., Choi, Y.J., Jung, S.H., Nam, Y.A., Zhang, Y., Yun, S.H., Chang, T.S., Lee, B.H. (2022). SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation. Theranostics, 12(5), 2351-2369. https://doi.org/10.7150/thno.70692.

ACS
Lee, W.; Kim, H.Y.; Choi, Y.J.; Jung, S.H.; Nam, Y.A.; Zhang, Y.; Yun, S.H.; Chang, T.S.; Lee, B.H. SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation. Theranostics 2022, 12 (5), 2351-2369. DOI: 10.7150/thno.70692.

NLM
Lee W, Kim HY, Choi YJ, Jung SH, Nam YA, Zhang Y, Yun SH, Chang TS, Lee BH. SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation. Theranostics 2022; 12(5):2351-2369. doi:10.7150/thno.70692. https://www.thno.org/v12p2351.htm

CSE
Lee W, Kim HY, Choi YJ, Jung SH, Nam YA, Zhang Y, Yun SH, Chang TS, Lee BH. 2022. SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation. Theranostics. 12(5):2351-2369.

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