Sterol regulatory element binding protein 1: a mediator for high fat diet-induced hepatic gluconeogenesis and glucose intolerance in fish.

BACKGROUND

Sterol regulatory element binding protein 1 (SREBP1) is considered to be a crucial regulator for lipid synthesis in vertebrates. However, whether SREBP1 could regulate hepatic gluconeogenesis under high fat diet (HFD) condition is still unknown, and the underlying mechanism is also unclear.

OBJECTIVE

This study determined gluconeogenesis-related gene and protein expressions in response to HFD in large yellow croaker, and explored the role and mechanism of SREBP1 in regulating the related transcription and signaling.

METHODS

Croakers (mean weight 15.61 ± 0.10 g) were fed with diets containing 12% crude lipid (ND) or 18% crude lipid (HFD) for 10 weeks. The glucose tolerance, insulin tolerance, hepatic gluconeogenesis-related genes and proteins expressions were determined. To explore the role of SREBP1 in HFD-induced gluconeogenesis, SREBP1 was inhibited by pharmacological inhibitor (Fatostatin) or genetic knockdown in croaker hepatocytes under palmitic acid (PA) condition. To explore the underlying mechanism, luciferase reporter and ChIP assays were conducted in HEK293T cells. Data were analyzed by ANOVA or Student t test.

RESULTS

Compared with ND group, HFD increased the mRNA expressions of gluconeogenesis genes (2.40 to 2.60-fold) (P < 0.05) and reduced AKT phosphorylation level (0.28 to 0.34-fold) (P < 0.05) in croaker. However, inhibition of SREBP1 by Fatostatin addition or SREBP1 knockdown reduced the mRNA expressions of gluconeogenesis genes (P < 0.05) and increased AKT phosphorylation level (P < 0.05) in hepatocytes, compared with PA. Moreover, Fatostatin addition or SREBP1 knockdown also increased mRNA expressions of irs1 (P < 0.05) and reduced serine phosphorylation of IRS1 (P < 0.05). Furthermore, SREBP1 inhibited IRS1 transcriptions by binding to its promoter, and induced IRS1 serine phosphorylation by activating DAG-PKCε signaling.

CONCLUSIONS

This study reveals the role of SREBP1 in hepatic gluconeogenesis under HFD condition in croaker, which may provide a potential strategy for improving HFD-induced glucose intolerance.

Informations de copyright

Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests ☒ 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.