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Abstract

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).

Macrophages 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.

Therefore, 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.

Further, 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.

Furthermore, 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.

Thus, 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.

Thereby, 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.