GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration.

Yuwei Zhang, Xuefeng Zhou, Peihao Liu, Xueyang Chen, Jie Zhang, Hong Zhang, Sha Li, Yishu Chen, Xin Song, Jinghua Wang, Hang Zeng, Xiaofen Zhang, Chenxi Tang, Chaohui Yu, Youming Li, Chengfu Xu

American journal of physiology. Gastrointestinal and liver physiology 2021 Apr 01

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Granulocyte colony stimulating factor (GCSF) is a cytokine with immunomodulation effects. However, little is known about its role in metabolic diseases. In the current study, we aimed to explore the role of GCSF in nonalcoholic fatty liver disease (NAFLD). Male GCSF-/- mice were used to investigate the function of GCSF in vivo after high-fat diet (HFD). Primary hepatocytes were used for evaluating the function of GCSF in vitro. Liver immune cells were isolated and analyzed by flow cytometry. Our results showed that GCSF administration significantly increased serum triglyceride (TG) levels in patients. Circulating GCSF was markedly elevated in HFD-fed mice. GCSF-/- mice exhibited alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis. Extra administration of GCSF significantly aggravated palmitic acid (PA)-induced lipid accumulation in primary hepatocytes. Mechanically, GCSF could bind to granulocyte colony stimulating factor receptor (GCSFR) and regulate suppressors of cytokine signaling 3, Janus kinase, signal transducer and activator of transcription 3 (SOCS3-JAK-STAT3) pathway. GCSF also enhanced hepatic neutrophils and macrophages infiltration, thereby modulating NAFLD. These findings suggest that GCSF plays an important regulatory role in NAFLD and may be a potential therapeutic target for NAFLD.NEW & NOTEWORTHY We found GCSF was involved in lipid metabolism and NAFLD development. GCSF administration increased serum triglyceride levels in patients. GCSF deficiency alleviated HFD-induced insulin resistance and hepatic steatosis in mice. GCSF could directly act on hepatocytes through GCSFR-SOCS3-JAK-STAT3 pathway, and regulate the infiltration of immune cells into the liver to indirectly modulate NAFLD. Our finding indicates that GCSF may provide new strategies for the treatment of NAFLD.

Citation

Yuwei Zhang, Xuefeng Zhou, Peihao Liu, Xueyang Chen, Jie Zhang, Hong Zhang, Sha Li, Yishu Chen, Xin Song, Jinghua Wang, Hang Zeng, Xiaofen Zhang, Chenxi Tang, Chaohui Yu, Youming Li, Chengfu Xu. GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration. American journal of physiology. Gastrointestinal and liver physiology. 2021 Apr 01;320(4):G531-G542