Work

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

Year: 2024

Type: article

Abstract: 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. 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. 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. 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. • 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.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2024.117531

Authors: Piotr Zabielski, Kamila Roszczyc-Owsiejczuk, Monika Imierska, Karolina Pogodzińska, Agnieszka U. Błachnio-Zabielska

Institution: Medical University of Białystok

Language: English

Topic: Lipid metabolism and biosynthesis

Subfield: Biochemistry

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,420