期刊
SCIENTIFIC REPORTS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep20405
关键词
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资金
- Swiss National Science Foundation [310030_141070/1, 31003A_159582/1]
- Swiss Heart Foundation
- National Centre of Competence in Research Program (NCCR-Kidney.CH)
- Chinese Scholarship Council
- Swiss National Science Foundation (SNF) [310030_141070, 31003A_159582] Funding Source: Swiss National Science Foundation (SNF)
Nonalcoholic fatty liver disease (NAFLD) associates with obesity and type 2 diabetes. Hypoactive AMP-activated protein kinase (AMPK), hyperactive mammalian target of rapamycin (mTOR) signaling, and macrophage-mediated inflammation are mechanistically linked to NAFLD. Studies investigating roles of arginase particularly the extrahepatic isoform arginase-II (Arg-II) in obesity-associated NAFLD showed contradictory results. Here we demonstrate that Arg-II-/- mice reveal decreased hepatic steatosis, macrophage infiltration, TNF-alpha and IL-6 as compared to the wild type (WT) littermates fed high fat diet (HFD). A higher AMPK activation (no difference in mTOR signaling), lower levels of lipogenic transcription factor SREBP-1c and activity/expression of lipogenic enzymes were observed in the Arg-II-/- mice liver. Moreover, release of TNF-alpha and IL-6 from bone marrow-derived macrophages (BMM) of Arg-II-/- mice is decreased as compared to WT-BMM. Conditioned medium from Arg-II-/- BMM exhibits weaker activity to facilitate triglyceride synthesis paralleled with lower expression of SREBP-1c and SCD-1 and higher AMPK activation in hepatocytes as compared to that from WT-BMM. These effects of BMM conditioned medium can be neutralized by neutralizing antibodies against TNF-alpha and IL-6. Thus, Arg-II-expressing macrophages facilitate diet-induced NAFLD through TNF-alpha and IL-6 in obesity.
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