| dc.description.abstract | One third of non-alcoholic fatty liver disease (NAFLD) progresses to its inflammatory subtype called non-alcoholic steatohepatitis (NASH). Liver macrophage-mediated inflammation contributes to the pathogenesis of NASH. However, their associated pathophysiology and the molecular mechanisms remain unclear. Osr1 is a transcription factor containing four C2H2-type zinc finger motifs. Our previous data described that Osr1 could regulate hepatic inflammation and cell survival in the progression of NAFLD in a pre-cancer model. And Osr1 is strongly expressed in hepatic macrophages during NAFLD pathogenesis. In this study, we investigated the physiological function and possible hepatoprotection role of Osr1 in macrophages on NAFLD development in high-fat diet (HFD) and Methionine/Choline deficient diet (MCD) diet treated mice.
Specifically deleting Osr1 in myeloid cells promoted NASH development, evidenced by severer liver inflammation and steatosis, suggesting a protective effect of Osr1 against NASH. Deleting Osr1 in macrophages induced more inflammation both in vivo and in vitro, associated with phenotype switch towards inflammatory, suggesting Osr1 might maintain macrophages toward alternative M2 like profile. Our RNA sequencing of the wild type and Osr1 myeloid knockout mice liver showed Osr1-dependent expression of genes and signaling pathways involved in macrophage polarization. In cultured bone marrow derived macrophages (BMDMs) for in vitro polarization study, Osr1 expression was found positively correlated with the M2 marker genes such as PPAR-γ in macrophage phenotype switch (M0/M1/M2), confirmed the role of Osr1 in maintaining macrophage M2 polarization. We also investigated the role of Osr1 in the macrophage metabolic reprogramming. Deleting Osr1 shift the macrophages to a glycolysis dependent ATP production profile. Further experiment also indicated that Osr1 is highly involved in the palmitate oxidation. Additionally, PPAR-γ was identified as the downstream targets of Osr1 by CHIP-qPCR and luciferase reporter assays. While compound heterozygotes of macrophage PPAR-γ and Osr1 promoted NASH progression, PPAR-γ agonist treatment inhibited the NASH progression, suggesting the functional Osr1-PPAR-γ axis in the liver macrophages for NASH progression. Upon establishing the role of Osr1 in macrophage alternative polarization, we performed the macrophage- hepatocytes coculture experiment and confirmed the effect of Osr1-null macrophages in inducing the hepatocytes inflammation and fat deposition.
In summary, we demonstrated that macrophage Osr1 plays an important role in hepatic inflammation and NASH progression via mediating macrophage activation. | en |
