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

## TL;DR

This study explores how LPE levels drop in a mouse model of fatty liver disease, linking it to increased Pnpla6/7 activity and liver inflammation.

## Contribution

The study identifies Pnpla6/7-driven LPE catabolism as a novel mechanism contributing to LPE depletion in MASH.

## Key findings

- HFCC/CDX mice showed reduced LPE levels in plasma and liver, correlating with liver inflammation.
- LPE degradation was linked to upregulated Pnpla6/7 in the liver of MASH mice.
- LPE depletion was associated with cholesterol and oxidized triglyceride accumulation in the liver.

## 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.