Enpp1 ameliorates MAFLD by regulating hepatocyte lipid metabolism through the AMPK/PPARα signaling pathway.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the leading chronic liver disease globally, and there are no approved pharmacotherapies to treat this disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) has been found to be related to insulin resistance and lipid accumulation. However, the role and mechanism of Enpp1 in the development of MAFLD remain unknown.

Results: Here we discovered that Enpp1 is lowly expressed in the liver of MAFLD patients by clinical investigation. Knocking out Enpp1 in the liver of mice aggravated obesity, insulin resistance and hepatic steatosis, and these effects were reversed by liver-specific Enpp1 overexpression. Through transcriptomic data mining and experimental validation, we demonstrated that Enpp1 deficiency inhibited the expression of AMPK (energy receptor) and PPARα (nuclear transcription factor for lipid metabolism), thereby promoting the transcription of lipid synthesis factors and mediating the progression of MAFLD. Mechanistically, Enpp1 enhanced the activity of AMPK by increasing the AMP-to-ATP ratio, which in turn raised PPARα levels and promoted the transcription of its downstream lipid metabolism factors. Pharmacological inhibition of AMPK activity abolished the promoting effect of Enpp1 on PPARα protein expression.

Conclusions: This study indicate that Enpp1 can effectively ameliorate MAFLD through effects on AMPK/PPARα signaling pathway-mediated lipid metabolism, revealing the significance of Enpp1 as a promising therapeutic target against MAFLD.