1. Academic Validation
  2. Rab7a-mTORC1 signaling-mediated cholesterol trafficking from the lysosome to mitochondria ameliorates hepatic lipotoxicity induced by aflatoxin B1 exposure

Rab7a-mTORC1 signaling-mediated cholesterol trafficking from the lysosome to mitochondria ameliorates hepatic lipotoxicity induced by aflatoxin B1 exposure

  • Chemosphere. 2023 Apr;320:138071. doi: 10.1016/j.chemosphere.2023.138071.
Jin-Xian Lin 1 Chi-Yu Xu 1 Xin-Mou Wu 1 Lin Che 1 Ting-Yu Li 1 Su-Min Mo 1 Dong-Bei Guo 1 Zhong-Ning Lin 2 Yu-Chun Lin 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, China.
  • 2 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, China. Electronic address: linzhn@xmu.edu.cn.
  • 3 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, China. Electronic address: linych@xmu.edu.cn.
Abstract

Aflatoxin B1 (AFB1) is a common contaminant in many foodstuffs and is considered a public health concern worldwide due to its hepatotoxicity caused by lipid metabolism disorders. However, the molecular mechanism underlying AFB1-induced lipotoxicity-dependent liver injury via regulating Cholesterol metabolism remains unclear. We established a Cholesterol trafficking disorder-mediated hepatic lipotoxicity model with AFB1 mixture exposure in vitro (HepaRG and HepG2 cells, 1.6 μM for 36 h) and in vivo (C57BL/6 mice, 3 mg kg-1, i.g., every other day for 6 weeks). In vitro, the interaction between lysosomal Niemann-Pick type C1 (NPC1) protein and mitochondrial translocator protein (TSPO) regulated lipotoxicity induced by AFB1 mixture exposure, including lysosomal membrane permeabilization and mitochondria-dependent Necroptosis. Moreover, the downregulation of lysosomal Ras-associated protein 7a (Rab7a) enhanced the mammalian target of rapamycin complex 1 (mTORC1)-mediated disorders of Cholesterol trafficking from the lysosome to mitochondria. Furthermore, Cholesterol trafficking disorder-mediated hepatic lipotoxicity induced by the low-dose level of AFB1 exposure was relieved by genetic or pharmaceutic activation of Rab7a to inhibit mTORC1 in vitro and ex vivo. In vivo, mTORC1 Inhibitor (Torin1, 4 mg kg-1, i.p., every other day for 3 weeks) alleviated the Cholesterol trafficking disorder-mediated hepatic lipotoxicity via upregulating the molecular machinery of lysosomes and mitochondria contact mediated by NPC1 and TSPO interaction in the low dose of AFB1 exposure. Altogether, our data suggested a novel mechanism that lysosomal Rab7a-mTORC1 signaling determined the Cholesterol trafficking regulated by NPC1-TSPO from the lysosome to mitochondria, which promoted hepatic lipotoxicity via lysosomal quality control and mitochondria-dependent Necroptosis signaling pathways in chemical mixture exposure.

Keywords

Aflatoxin B1 (AFB1); Cholesterol trafficking; Hepatic lipotoxicity; Lysosomes and mitochondria contact; Mammalian target of rapamycin complex 1 (mTORC1); Ras-associated protein 7a (Rab7a).

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