Nonalcoholic fatty liver disease (NAFLD) is considered 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 bioinformatics analyses followed by functional testing, we demonstrate that hepatic expression of coagulation factor VII (FVII) decreases in patients and mice with NAFLD/nonalcoholic steatohepatitis (NASH). By using adenovirus-mediated F7-knockdown and hepatocyte-specific F7-knockout mouse models, our mechanistic investigations unveil a noncoagulant function of hepatic FVII in mitigating lipid accumulation and lipotoxicity. This protective effect is achieved through the suppression of fatty acid uptake, orchestrated via the AKT-CD36 pathway. Interestingly, 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 F7 results 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.
Coagulation factor VII (FVII) abundance is significantly decreased during nonalcoholic fatty liver disease and negatively correlated with nonalcoholic fatty liver disease progression.
Hepatic F7 deficiency exacerbates high-fat diet–induced liver steatosis.
Deficiency of F7 accelerates fatty acid uptake via AKT-mediated CD36 upregulation in hepatocytes.
FVII directly interacts with PP2A and AKT, triggering the dephosphorylation of AKT by PP2A.
Hepatocyte-specific overexpression of F7 ameliorates liver steatosis.
This article contains supplementary material online at https://doi.org/10.2337/figshare.25259953.
