<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The role of the macrophage mTOR-S6K axis effectors –S6K1 and S6K2– in NASH, NASH-HCC and liver fibrosis"^^ . "Excess nutrients can be temporarily stored in the liver in the form of fatty acids and glycogen; however, a chronic positive energy state induces pathological storage of fatty acids in hepatocytes, driving inflammation and leading to non-alcoholic steatohepatitis (NASH).\r\n\r\nMacrophages are pivotal for the liver homeostasis, they have distinct roles in NASH, and its complications like NASH-HCC and liver fibrosis. Bridging nutrient sensing and macrophages, the mammalian target of rapamycin (mTOR) is involved in macrophage polarization, but mTOR-inhibition in macrophages has shown conflicting evidence for the treatment of NASH. Additionally, the role of downstream mTOR-effectors S6K1 and S6K2 in the macrophage compartment in NASH-associated carcinogenesis is unknown.\r\n\r\nTherefore, to investigate the role of macrophage mTOR-S6K effectors –S6K1 and S6K2– I studied the activation status of myeloid mTOR-S6K axis in human and mice healthy and NASH livers where I found it to be increased relative to the pathology severity.\r\n\r\nFurther, I established two independent transgenic mousselines with deletion of S6K1 and S6K2 in mature macrophages and monocytes. I then generated bone-marrow derived macrophages from these mice to explore the role of the S6 kinases in macrophage polarization, where I found no causal link between S6K1/S6K2 and macrophage polarization.\r\n\r\nFurthermore, to explore the role of both macrophage kinases in vivo, I employed chronic inflammation models of NASH and NASH-HCC either in the context of metabolic syndrome (Western diet feeding) or in the context of profound liver fibrosis (Choline-deficient L-amino acid-defined diet feeding). These experiments showed no causal link between macrophage S6K1/S6K2 in obesity, metabolic syndrome (i.e. glucose/insulin tolerance, obesity/body composition) and liver pathology beyond the progression of liver fibrosis.\r\n\r\nThus, to understand the role of macrophage S6K1/S6K2 in liver fibrosis, I used a hepatotoxic model of carbon tetrachloride (CCl4) to induce liver fibrosis in mice with macrophages lacking the S6 kinases in myeloid cells. My data demonstrated that the macrophage S6 kinases play a subdued role in liver fibrosis.\r\n\r\nThereby, my work demonstrated that the myeloid mTOR-S6K axis is activated in human and mouse NASH. While not influencing NASH-progression or NASH-HCC, macrophage S6K1/S6K2 loss dampened liver fibrosis in NASH and CCl4-induced liver injury. My data contributes to resolving conflicting evidence surrounding the role of the myeloid mTOR-S6K axis in obesity, NASH, NASH-HCC and liver fibrosis."^^ . "2025" . . . . . . . "Jose Efren"^^ . "Barragan Avila"^^ . "Jose Efren Barragan Avila"^^ . . . . . . "The role of the macrophage mTOR-S6K axis effectors –S6K1 and S6K2– in NASH, NASH-HCC and liver fibrosis (PDF)"^^ . . . "The role of the macrophage mTOR-S6K axis effectors –S6K1 and S6K2– in NASH, NASH-HCC and liver fibrosis (Other)"^^ . . . . . . "The role of the macrophage mTOR-S6K axis effectors –S6K1 and S6K2– in NASH, NASH-HCC and liver fibrosis (Other)"^^ . . . . . . "The role of the macrophage mTOR-S6K axis effectors –S6K1 and S6K2– in NASH, NASH-HCC and liver fibrosis (Other)"^^ . . . . . . "The role of the macrophage mTOR-S6K axis effectors –S6K1 and S6K2– in NASH, NASH-HCC and liver fibrosis (Other)"^^ . . . . . . "The role of the macrophage mTOR-S6K axis effectors –S6K1 and S6K2– in NASH, NASH-HCC and liver fibrosis (Other)"^^ . . . . . "HTML Summary of #34635 \n\nThe role of the macrophage mTOR-S6K axis effectors –S6K1 and S6K2– in NASH, NASH-HCC and liver fibrosis\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . . . "610 Medizin"@de . "610 Medical sciences Medicine"@en . .