Regulation of hepatic mitochondrial function by AIBP mitigates MASLD development

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial disorder characterized by dysregulated lipid metabolism, hepatic inflammation, oxidative stress, and mitochondrial dysfunction. Emerging evidence suggests that apolipoprotein A-I binding protein (AIBP) regulates mitochondrial quality control and protects against oxidative stress in chronic inflammatory conditions. This study aimed to determine whether AIBP preserves hepatic mitochondrial function and thereby mitigates MASLD progression.

In the present study, we demonstrate that mitochondrial AIBP expression is significantly reduced in the livers of patients with metabolic dysfunction-associated steatohepatitis (MASH). Using an AMLN diet-induced mouse model, we found that AIBP deficiency exacerbates hepatic steatosis, adipose tissue expansion, and lipid droplet (LD) accumulation. Notably, loss of AIBP was associated with reduced mitochondrial number and size, altered expression of mitochondrial proteins, and decreased LD-mitochondria contacts in the liver, as determined by electron microscopy (EM). Furthermore, AIBP improved mitochondrial function and reduced LD accumulation in vitro. Restoration of AIBP expression by adeno-associated virus (AAV)-mediated gene delivery attenuated AMLN diet-induced MASLD progression in vivo.

These findings identify AIBP as a critical regulator of hepatic mitochondrial function and lipid metabolism. AIBP deficiency promotes mitochondrial dysfunction and exacerbates MASLD progression, whereas AIBP restoration confers protection against hepatic steatosis. Collectively, these results support AIBP as a potential therapeutic target for preventing the progression of MASLD to MASH.