α1-acid Glycoprotein mitigates MASLD progression by modulating liver and adipose tissue function.

Dysregulation of hepatokines has been observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting their involvement in disease progression. In this study, we aimed to investigate the role of α1-acid glycoprotein (AGP), a hepatokine, in the progression of MASLD and to evaluate its potential therapeutic utility. Reanalysis of hepatic RNA sequencing datasets from patients with fatty liver disease showed that expression of the hepatic AGP gene decreased with disease progression. A high-fat diet (HFD)-induced mouse model of MASLD also showed decreased plasma and hepatic AGP levels. Whole-body AGP-knockout (AGP-KO) mice were fed a HFD for 12 weeks. Compared to wild-type mice, AGP-KO mice fed a HFD displayed further exacerbated hepatic steatosis, obesity, adipose tissue inflammation, and impaired glucose tolerance, suggesting a protective role for endogenous AGP against MASLD. Morphological abnormalities of hepatic mitochondria were observed in AGP-KO mice. Human-derived AGP (hAGP) was isolated and purified from plasma fraction V supernatant derived from human blood donations using ion-exchange column chromatography. hAGP exerted a protective effect against palmitate-induced lipotoxicity in hepatocytes, adipocytes, and macrophages. Exogenous administration of hAGP to MASLD mice attenuated disease progression by reducing hepatic mitochondrial dysfunction and adipose tissue inflammation. In conclusion, decreased endogenous AGP levels may contribute to the disease progression of MASLD. AGP has the potential to serve as a novel therapeutic agent against MASLD by targeting both liver and adipose tissue.