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

Autor:	Lee W; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Kim HY; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Choi YJ; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Jung SH; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Nam YA; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Zhang Y; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Yun SH; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Chang TS; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Lee BH; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Jazyk:	angličtina
Zdroj:	Theranostics [Theranostics] 2022 Feb 21; Vol. 12 (5), pp. 2351-2369. Date of Electronic Publication: 2022 Feb 21 (Print Publication: 2022).
DOI:	10.7150/thno.70692
Abstrakt:	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. Competing Interests: Competing Interests: The authors have declared that no competing interest exists. (© The author(s).)
Databáze:	MEDLINE
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