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Cited by 155Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

Macrophage-derived osteopontin (SPP1) protects from nonalcoholic steatohepatitis

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Han, Hui, Ge, Xiaodong, Komakula, Sai Santosh Babu, Desert, Romain, Das, Sukanta, Song, Zhuolun, Chen, Wei, Athavale, Dipti +4 more·2023·Gastroenterology
DOI 10.1053/j.gastro.2023.03.228PMC PMC10986640
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Abstract

Background & Aims 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. Methods 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. Results 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. Conclusion 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.

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Cited by

Sorted by citations

Authors
Han, H., Ge, X., Komakula, S. S. B., Desert, R., Das, S., Song, Z., Chen, W., Athavale, D., Gaskell, H., Lantvit, D., Guzman, G., & Nieto, N.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Nieto, Natalia
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2023-07
Volume
165
Issue
1
Pages
201-217
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2023.03.228
PMC
PMC10986640
OpenAlex
W4362606298
Cited by
155
References
3
Citations by year
2026: 49 · 2025: 52 · 2024: 45 · 2023: 9
FWCI
30.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Michael Reese Health Trust
  • American Association for the Study of Liver Diseases
  • U.S. Public Health Service (DK134461)
  • University of Illinois at Chicago
  • Cancer Center, University of Illinois at Chicago
  • National Institute of Diabetes and Digestive and Kidney Diseases
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
osteopontin, nonalcoholic steatohepatitis, hepatic macrophages, arginase II, oncostatin M, STAT3 signaling, fatty acid oxidation, steatosis, myeloid cells, non-alcoholic fatty liver disease
MeSH terms
Animals, Disease Models, Animal, Female, Liver, Liver Cirrhosis, Macrophages, Male, Mice, Inbred C57BL, Mice, Osteopontin, Diet, High-Fat, Non-alcoholic Fatty Liver Disease, Diet, Western

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