Lipotoxicity-induced STING1 activation stimulates MTORC1 and restricts hepatic lipophagy.

ABSTRACT

Lipid accumulation often leads to lipotoxic injuries to hepatocytes, which can cause nonalcoholic steatohepatitis. The association of inflammation with lipid accumulation in liver tissue has been studied for decades; however, key mechanisms have been identified only recently. In particular, it is still unknown how hepatic inflammation regulates lipid metabolism in hepatocytes. Herein, we found that PA treatment or direct stimulation of STING1 promoted, whereas STING1 deficiency impaired, MTORC1 activation, suggesting that STING1 is involved in PA-induced MTORC1 activation. Mechanistic studies revealed that STING1 interacted with several components of the MTORC1 complex and played an important role in the complex formation of MTORC1 under PA treatment. The involvement of STING1 in MTORC1 activation was dependent on SQSTM1, a key regulator of the MTORC1 pathway. In SQSTM1-deficient cells, the interaction of STING1 with the components of MTORC1 was weak. Furthermore, the impaired activity of MTORC1 via rapamycin treatment or STING1 deficiency decreased the numbers of LDs in cells. PA treatment inhibited lipophagy, which was not observed in STING1-deficient cells or rapamycin-treated cells. Restoration of MTORC1 activity via treatment with amino acids blocked lipophagy and LDs degradation. Finally, increased MTORC1 activation concomitant with STING1 activation was observed in liver tissues of nonalcoholic fatty liver disease patients, which provided clinical evidence for the involvement of STING1 in MTORC1 activation. In summary, we identified a novel regulatory loop of STING1-MTORC1 and explain how hepatic inflammation regulates lipid accumulation. Our findings may facilitate the development of new strategies for clinical treatment of hepatic steatosis.Abbreviations AA amino acid; ACTB actin beta; cGAMP cyclic GMP-AMP; CGAS cyclic GMP-AMP synthase; DEPTOR DEP domain containing MTOR interacting protein; EIF4EBP1 eukaryotic translation initiation factor 4E binding protein 1; FFAs free fatty acids; GFP green fluorescent protein; HFD high-fat diet; HT-DNA herring testis DNA; IL1B interleukin 1 beta; LAMP1 lysosomal associated membrane protein 1; LDs lipid droplets; MAP1LC3 microtubule associated protein 1 light chain 3; MAP1LC3B microtubule associated protein 1 light chain 3 beta; MEFs mouse embryonic fibroblasts; MLST8 MTOR associated protein, LST8 homolog; MT-ND1 mitochondrially encoded NADH ubiquinone oxidoreductase core subunit 1; mtDNA mitochondrial DNA; MTOR mechanistic target of rapamycin kinase; MTORC1 MTOR complex 1; NAFL nonalcoholic fatty liver; NAFLD nonalcoholic fatty liver disease; NASH nonalcoholic steatohepatitis; NPCs non-parenchymal cells; PA palmitic acid; PLIN2 perilipin 2; RD regular diet; RELA RELA proto-oncogene, NF-kB subunit; RPS6 ribosomal protein S6; RPS6KB1 ribosomal protein S6 kinase B1; RPTOR regulatory associated protein of MTOR complex 1; RRAGA Ras related GTP binding A; RRAGC Ras related GTP binding C; SQSTM1 sequestosome 1; STING1 stimulator of interferon response cGAMP interactor 1; TBK1 TANK binding kinase 1; TGs triglycerides; TREX1 three prime repair exonuclease 1.