Sterol Regulatory Element Binding Protein 1: A Mediator for High-Fat Diet-Induced Hepatic Gluconeogenesis and Glucose Intolerance in Fish

Zengqi Zhao; Xiaojun Xiang; Qiang Chen; Jianlong Du; Si Zhu; Xiang Xu; Yanan Shen; Shunlang Wen; Yueru Li; Wei Xu; Kangsen Mai; Qinghui Ai

doi:10.1016/j.tjnut.2024.02.031

Sterol Regulatory Element Binding Protein 1: A Mediator for High-Fat Diet-Induced Hepatic Gluconeogenesis and Glucose Intolerance in Fish

J Nutr. 2024 Mar 7:S0022-3166(24)00154-8. doi: 10.1016/j.tjnut.2024.02.031. Online ahead of print.

Authors

Zengqi Zhao¹, Xiaojun Xiang¹, Qiang Chen¹, Jianlong Du¹, Si Zhu¹, Xiang Xu¹, Yanan Shen¹, Shunlang Wen¹, Yueru Li¹, Wei Xu¹, Kangsen Mai¹, Qinghui Ai²

Affiliations

¹ Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, Shandong, China.
² Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, Shandong, China. Electronic address: qhai@ouc.edu.cn.

PMID: 38460786
DOI: 10.1016/j.tjnut.2024.02.031

Abstract

Background: Sterol regulatory element binding protein (SREBP) 1 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.

Objectives: This study aimed to determine gluconeogenesis-related gene and protein expressions in response to HFD in large yellow croaker and explore 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 [control diet (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 pharmacologic inhibitor (fatostatin) or genetic knockdown in croaker hepatocytes under palmitic acid (PA) condition. To explore the underlying mechanism, luciferase reporter and chromatin immunoprecipitation assays were conducted in HEK293T cells. Data were analyzed using analysis of variance or Student t test.

Results: Compared with ND, HFD increased the mRNA expressions of gluconeogenesis genes (2.40-fold to 2.60-fold) (P < 0.05) and reduced protein kinase B (AKT) phosphorylation levels (0.28-fold to 0.34-fold) (P < 0.05) in croakers. However, inhibition of SREBP1 by fatostatin addition or SREBP1 knockdown reduced the mRNA expressions of gluconeogenesis genes (P < 0.05) and increased AKT phosphorylation levels (P < 0.05) in hepatocytes, compared with that by PA treatment. Moreover, fatostatin addition or SREBP1 knockdown also increased the 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 diacylglycerol-protein kinase Cε signaling.

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

Keywords: gluconeogenesis; high-fat diet; insulin receptor substrate 1; insulin signaling; sterol regulatory element binding protein 1.