Loss of Ambp ameliorates MASLD progression via generating protective ROS and activating PPAR signaling pathway

However, the roles of AMBP, the precursor of A1M and Bikunin, in the pathogenesis and progression of MASLD remain inadequately characterized.

Methods

In this study, we analyzed the AMBP expression across multiple MASLD related Gene Expression Omnibus (GEO) datasets. Utilizing zebrafish ambp-/- and mouse Ambp-/- mutants subjected to high-fat diet (HFD) feeding, we assessed hepatic lipid accumulation. Additionally, we measured reactive oxygen species (ROS) levels, glutathione peroxidase 4 (Gpx4), and malondialdehyde (MDA) expression, and performed RNA sequencing in HFD-fed ambp-/- zebrafish.

The roles of ROS were further investigated using the ROS inhibitor N-acetylcysteine (NAC) and the PPARα-specific inhibitor GW6471. Results: Our finding revealed that ambp deficiency mitigated the occurrence of MASLD under HFD conditions. Mechanistically, ambp deficiency induced the production of cytoprotective ROS, which subsequently activated the PPAR signaling pathway, thereby inhibiting oxidative stress and enhancing the mitochondrial fatty acid β-oxidation.

Conclusions: Collectively, our results demonstrate that AMBP serves as a critical regulator of MASLD pathogenesis. Inhibition of AMBP might be a promising therapeutic approach for the treatment of MASLD.