Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether MF-derived OPN affects NASH progression is unknown. We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose, and cholesterol diet mimicking the Western diet, to induce NASH. This study demonstrated that MFs with high expression of SPP1 are enriched in patients and mice with nonalcoholic fatty liver disease (NAFLD), and show metabolic but not pro-inflammatory properties. Conditional knockin of Spp1 in myeloid cells (Spp1 ^{KI Mye}) or in hepatic macrophages (Spp1 ^{KI LvMF}) conferred protection, whereas conditional knockout of Spp1 in myeloid cells (Spp1 ^ΔMye) worsened NASH. The protective effect was mediated by induction of arginase-2 (ARG2), which enhanced fatty acid oxidation (FAO) in hepatocytes. Induction of ARG2 stemmed from enhanced production of oncostatin-M (OSM) in MFs from Spp1 ^{KI Mye} mice. OSM activated STAT3 signaling, which upregulated ARG2. In addition to hepatic effects, Spp1 ^{KI Mye} also protected through sex-specific extrahepatic mechanisms. MF-derived OPN protects from NASH, by upregulating OSM, which increases ARG2 through STAT3 signaling. Further, the ARG2-mediated increase in FAO reduces steatosis. Therefore, enhancing the OPN–OSM–ARG2 crosstalk between MFs and hepatocytes may be beneficial for patients with NASH. Currently, there are no approved treatments for nonalcoholic steatohepatitis, making this a major unmet clinical need. Although dynamic changes in liver macrophage subsets during the pathogenesis of nonalcoholic steatohepatitis link these shifts to pathologic tissue remodeling, macrophages also have potential to reduce steatosis and fibrosis, an aspect of macrophage function that has been understudied. Thus, the significance of this proposal lies in the delineation, of the not previously known, protective role of osteopontin in macrophages in nonalcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]