Silencing the glycerol-3-phosphate acyltransferase-1 gene in the liver of mice fed a high-fat diet, enhances insulin sensitivity and glucose metabolism by promoting fatty acid beta-oxidation.

BACKGROUND

Liver plays a central role in systemic glucose and lipid metabolism. High-fat diet (HFD) and obesity are related to hepatic lipid accumulation and insulin resistance (InsR). Diacylglycerols (DAG) play a key role in the induction of InsR, however their involvement in hepatic InsR remains debated. This study aimed to clarify and confirm the role of glycero-3-phosphate acyltransferase 1 (GPAT1), a rate-limiting enzyme in DAG synthesis, in the progression of hepatic InsR in the context of HFD-induced lipid accumulation and insulin resistance in the liver.

METHODS

Liver-targeted GPAT1 silencing was performed using shRNA-mediated hydrodynamic gene delivery. Lipid species including LCA-CoA, sphingolipids, DAG and acyl-carnitines were quantified using UHPLC/MS/MS while insulin signalling was assessed at protein level by Western Blot. Hepatic glucose metabolism, including glucose-6-pasphate content and gluconeogenesis rate was evaluated using GC/MS.

RESULTS

HFD-fed animals developed InsR, evidenced by increased HOMA-IR, enhanced gluconeogenesis and reduced glycogen content compared to controls. Hepatic GPAT1 silencing in HFD-fed animals resulted in a significant reduction of DAG and TAG levels, increased acyl-carnitines content and upregulated mitochondrial β-oxidation protein expression. These changes were accompanied by improved insulin signalling, enhanced glycogen storage, and reduced gluconeogenesis.

CONCLUSIONS

Silencing GPAT1, and thereby reducing glycerolipid synthesis, promotes β-oxidation and ameliorates HFD-induced hepatic insulin resistance, confirming the enzyme's pivotal role in liver metabolic dysfunction associated with increased lipid supply.

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.