Rab7a-mTORC1 signaling-mediated cholesterol trafficking from the lysosome to mitochondria ameliorates hepatic lipotoxicity induced by aflatoxin B1 exposure. (April 2023)

• Record Type: Journal Article
• Authors: Lin, Jin-Xian; Xu, Chi-Yu; Wu, Xin-Mou; Che, Lin; Li, Ting-Yu; Mo, Su-Min; Guo, Dong-Bei; Lin, Zhong-Ning; Lin, Yu-Chun
• Is Part Of: Chemosphere. Volume 320(2023)
• Publication Date: 2023-04
• Subjects: Aflatoxin B1 (AFB1) -- Cholesterol trafficking -- Mammalian target of rapamycin complex 1 (mTORC1) -- Ras-associated protein 7a (Rab7a) -- Lysosomes and mitochondria contact -- Hepatic lipotoxicity; AFB1 aflatoxin B1 -- ER endoplasmic reticulum -- GEO gene expression omnibus -- HBx HBV x protein -- HFCD high-fat/cholesterol diet -- LAMP lysosome-associated membrane protein -- LD lipid droplet -- LMP lysosomal membrane permeabilization -- LyQC lysosomal quality control -- MCS membrane contact site -- MLKL mixed lineage kinase domain-like protein -- mTORC1 mammalian target of rapamycin complex 1 -- NAFLD nonalcoholic fatty liver disease -- NPC1 Niemann-Pick type C1 -- ox-LDL oxidized low-density lipoprotein -- Rab7a Ras-associated protein 7a -- Raptor regulatory associated protein of mTOR complex 1 -- RIPK receptor-interacting protein kinase -- StAR steroidogenic acute regulatory protein -- TSPO translocator protein; Pollution -- Periodicals; Pollution -- Physiological effect -- Periodicals; Environmental sciences -- Periodicals; Atmospheric chemistry -- Periodicals; 551.511
• DOI: 10.1016/j.chemosphere.2023.138071
• Languages: English
• ISSNs: 0045-6535

Abstract

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. Graphical abstract: Schematic view of study for the mechanism of Rab7a-mTORC1 signaling-mediated cholesterol trafficking from the lysosome to mitochondria ameliorates hepatic lipotoxicity induced by the environmental level of aflatoxin B1 exposure (Created in BioRender.com) Image 1 Highlights: AFB1 and HFCD exposure induced cholesterol trafficking disorder-mediated hepatic lipotoxicity. NPC1-TSPO interaction acted as molecular machinery tethering inter-lysosome-mitochondria contact. Lysosomal Rab7a-mTORC1 signaling regulated cholesterol-related LMP and necroptosis. Targeting intervention of mTORC1 prevented xenobiotics exposure-associated NAFLD.