{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Liu W"],"funding":["Tianjin Municipal Science and Technology Project","National Natural Science Foundation of China"],"pagination":["211-231"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6282883"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7(1)"],"pubmed_abstract":["<h4>Background & aims</h4>Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent nonalcoholic fatty liver disease, characterized by inflammatory cell infiltration and hepatocellular damage. Mammalian target of rapamycin complex 1 (mTORC1) has been investigated extensively in the context of cancer, including hepatocellular carcinoma. However, the role of mTORC1 in NASH remains largely unknown.<h4>Methods</h4>mTORC1 activity in macrophages in human mild and severe NASH liver was compared. Mice with macrophage-specific deletion of the regulatory-associated protein of mTOR (Raptor) subunit and littermate controls were fed a high-fructose, palmitate, and cholesterol diet for 24 weeks or a methionine- and choline-deficient diet for 4 weeks to develop NASH.<h4>Results</h4>We report that in human beings bearing NASH, macrophage mTORC1 activity was lower in livers experiencing severe vs mild NASH liver. Moreover, macrophage mTORC1 disruption exacerbated the inflammatory response in 2 diet-induced NASH mouse models. Mechanistically, in response to apoptotic hepatocytes (AHs), macrophage polarization toward a M2 anti-inflammatory phenotype was inhibited in Raptor-deficient macrophages. During the digestion of AHs, macrophage mTORC1 was activated and coupled with dynamin-related protein 1 to facilitate the latter's phosphorylation, leading to mitochondrial fission-mediated calcium release. Ionomycin or A23187, calcium ionophores, prevented Raptor deficiency-mediated failure of lysosome acidification and subsequent lipolysis. Blocking dynamin-related protein 1-dependent mitochondria fission impaired lysosome function, resulting in reduced production of anti-inflammatory factors such as interleukins 10 and 13.<h4>Conclusions</h4>Persistent mTORC1 deficiency in macrophages contributes to the progression of NASH by causing lysosome dysfunction and subsequently attenuating anti-inflammatory M2-like response in macrophages during clearance of AHs."],"journal":["Cellular and molecular gastroenterology and hepatology"],"pubmed_title":["Macrophage Raptor Deficiency-Induced Lysosome Dysfunction Exacerbates Nonalcoholic Steatohepatitis."],"pmcid":["PMC6282883"],"funding_grant_id":["81700506","14JCYBJC41800","81500445","81670388","81420108003","81770836"],"pubmed_authors":["Yao L","Yan J","Huang J","Zhu Y","Ye C","Wang C","Li Q","Wang H","Liu W","Liu Y","Zou Z","Ai D","Cheng Q","Zhang X"],"additional_accession":[]},"is_claimable":false,"name":"Macrophage Raptor Deficiency-Induced Lysosome Dysfunction Exacerbates Nonalcoholic Steatohepatitis.","description":"<h4>Background & aims</h4>Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent nonalcoholic fatty liver disease, characterized by inflammatory cell infiltration and hepatocellular damage. Mammalian target of rapamycin complex 1 (mTORC1) has been investigated extensively in the context of cancer, including hepatocellular carcinoma. However, the role of mTORC1 in NASH remains largely unknown.<h4>Methods</h4>mTORC1 activity in macrophages in human mild and severe NASH liver was compared. Mice with macrophage-specific deletion of the regulatory-associated protein of mTOR (Raptor) subunit and littermate controls were fed a high-fructose, palmitate, and cholesterol diet for 24 weeks or a methionine- and choline-deficient diet for 4 weeks to develop NASH.<h4>Results</h4>We report that in human beings bearing NASH, macrophage mTORC1 activity was lower in livers experiencing severe vs mild NASH liver. Moreover, macrophage mTORC1 disruption exacerbated the inflammatory response in 2 diet-induced NASH mouse models. Mechanistically, in response to apoptotic hepatocytes (AHs), macrophage polarization toward a M2 anti-inflammatory phenotype was inhibited in Raptor-deficient macrophages. During the digestion of AHs, macrophage mTORC1 was activated and coupled with dynamin-related protein 1 to facilitate the latter's phosphorylation, leading to mitochondrial fission-mediated calcium release. Ionomycin or A23187, calcium ionophores, prevented Raptor deficiency-mediated failure of lysosome acidification and subsequent lipolysis. Blocking dynamin-related protein 1-dependent mitochondria fission impaired lysosome function, resulting in reduced production of anti-inflammatory factors such as interleukins 10 and 13.<h4>Conclusions</h4>Persistent mTORC1 deficiency in macrophages contributes to the progression of NASH by causing lysosome dysfunction and subsequently attenuating anti-inflammatory M2-like response in macrophages during clearance of AHs.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019","modification":"2025-04-04T12:42:05.128Z","creation":"2019-03-27T00:13:43Z"},"accession":"S-EPMC6282883","cross_references":{"pubmed":["30539788"],"doi":["10.1016/j.jcmgh.2018.09.011"]}}