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 - 08/11/24
Abstract |
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.
El texto completo de este artículo está disponible en PDF.Graphical Abstract |
Highlights |
• | HFD animals develop InsR, manifested by elevated HOMA-IR, increased gluconeogenesis, and decreased hepatic glycogen content. |
• | GPAT1 silencing in the liver of HFD animals decreases accumulation of DAG and TAG and increases content of acylcarnitines. |
• | Reduction of hepatic DAG augments insulin signaling, decreases the rate of gluconeogenesis and an increases glycogen content. |
• | GPAT1 silencing in liver up-regulates expression of proteins involved in β-oxidation and attenuates HFD-induced hepatic InsR. |
Keywords : Diacylglycerol, Gene silencing, Gluconeogenesis, Glucose metabolism, Insulin resistance, Lipid metabolism, Liver, Mass spectrometry
Esquema
Vol 180
Artículo 117531- novembre 2024 Regresar al número
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Bienvenido a EM-consulte, la referencia de los profesionales de la salud.
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