Lysophosphatidylethanolamine Degradation Associated with Upregulation of Pnpla6/7 in a Murine Model of Metabolic Dysfunction-Associated Steatohepatitis.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a form of fatty liver disease characterized by fat accumulation, hepatic inflammation, and fibrosis. Lysophosphatidylethanolamine (LPE), a partially deacylated product of phosphatidylethanolamine, plays significant roles in anti-inflammatory responses and mitochondrial homeostasis. Although serum LPE levels are reduced in patients with MASH, the underlying mechanisms remain unclear. In this study, we investigated LPE metabolism using liquid chromatography-tandem mass spectrometry and protein expressions in MASH mice. Male C57BL/6J mice were fed a high-fat, high-cholesterol, and cholic acid diet, along with 2% hydroxypropyl-β-cyclodextrin in drinking water (HFCC/CDX) for three weeks to induce MASH. LPE was primarily distributed in the liver and kidneys, with lower levels in the white adipose tissue. HFCC/CDX mice exhibited accumulation of cholesterols and oxidized triglycerides, accompanied by inflammation and fibrosis in the liver. In the plasma and liver of HFCC/CDX mice, most LPE species were decreased and showed negative correlations with hepatic inflammation, with the exception of LPE 18:1. Mechanistically, enhanced degradation of LPE to glycerophosphorylethanolamine was associated with upregulation of Pnpla6/7 in the liver. These findings suggest that Pnpla6/7-driven LPE catabolism is contributing to LPE depletion. This study provides a new perspective to understand the association between disrupted phospholipid metabolism and MASH pathogenesis.