Hepatic ASPG-mediated lysophosphatidylinositol catabolism impairs insulin signal transduction.

ABSTRACT: Bioactive glycerolysophospholipids (GLPs) are implicated in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity; however, the mechanisms underlying glycerolysophospholipid-mediated changes in insulin signaling remain poorly understood. Here, we identify the amino acid-metabolism enzyme asparaginase (ASPG) as a critical regulator of systemic fatty acid handling and insulin signal transduction. Hepatic ASPG expression levels negatively correlate with insulin sensitivity in humans. Loss of Aspg in MASLD mice modifies the liver hepatokine secretome, enhancing systemic insulin sensitivity. Notably, ASPG bears lysophospholipase activity towards the bioactive lipid lysophosphatidylinositol (LPI) in vitro and in vivo. Mechanistically, Aspg deficiency re

SUBMITTER: Li F 

PROVIDER: S-EPMC12436650 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature