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Coagulation factor FVII fine-tunes hepatic steatosis by blocking AKT-CD36-mediated fatty acid uptake

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posted on 2024-02-23, 20:21 authored by Yao Zhang, Quanxin Jiang, Xingxing Liang, Qiqi Qian, Jie Xiong, Chuchu Liu, Junting Xu, Ning Wang, Ying Xu, Peihui Zhou, Sijia Lu, Qian Zhou, Yanmei Yuan, Xuemei Fan, Junli Liu, Suzhen Chen

NAFLD is considered as a risk factor for cardiovascular and cerebrovascular disease owing to its close association with coagulant disturbances. However, the precise biological functions and mechanisms that connect coagulation factors to NAFLD pathology remain inadequately understood. Herein, with unbiased bioinformatic analyses followed by functional test, we demonstrate that hepatic expression of coagulation factor FVII decreases in patients and mice with NAFLD/NASH. By employing adenovirus-mediated F7-knockdown and hepatocyte-specific F7-knockout mouse models, our mechanistic investigations unveil a non-coagulant function of hepatic FVII in mitigating lipid accumulation and lipotoxicity. This protective effect is achieved through the suppression of fatty acid (FA) uptake, orchestrated via the AKT-CD36 pathway. Interestingly, we observed that intracellular FVII directly interacts with AKT and PP2A, thereby promoting their association and triggering the dephosphorylation of AKT. Therapeutic intervention through adenovirus-mediated liver-specific overexpression of FVII has resulted in noteworthy improvements in liver steatosis, inflammation, injury and fibrosis in severely afflicted NAFLD mice. In conclusion, our findings highlight coagulation factor FVII as a critical regulator of hepatic steatosis and a potential target for the treatment of NAFLD and NASH.

Funding

This work was supported by the National Natural Science Foundation of China (82170863, 82330026, 92357303); National Key R&D Program of China (2021YFA0804800, 2018YFA0800600); Shanghai Municipal Commission of Science and Technology (21QA1407000; 20SG10); Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20212501); Lingang Laboratory, Grant (LG-QS-202205-06); National Facility for Translational Medicine (Shanghai) (TMSK-2020-102); Shanghai Sixth People's Hospital (ynyq202103; ynjq202102).

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