2. Academic Validation
  3. F6P/G6P-mediated ChREBP activation promotes the insulin resistance-driven hepatic lipid deposition in zebrafish

F6P/G6P-mediated ChREBP activation promotes the insulin resistance-driven hepatic lipid deposition in zebrafish

  • J Nutr Biochem. 2023 Sep 23;109452. doi: 10.1016/j.jnutbio.2023.109452.
Yulong Gong 1,  Qisheng Lu 2,  Longwei Xi 2,  Yulong Liu 2,  Bingyuan Yang 3,  Jingzhi Su 2,  Haokun Liu 1,  Junyan Jin 1,  Zhimin Zhang 1,  Yunxia Yang 1,  Xiaoming Zhu 1,  Shouqi Xie 4,  Dong Han 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
  • 2 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 4 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; The Innovative Academy of Seed Design, Chinese Academy of Sciences, Wuhan 430072, China.
  • 5 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Hubei Hongshan Laboratory, Wuhan 430070, China. Electronic address: [email protected].
PMID: 37748621 DOI: 10.1016/j.jnutbio.2023.109452
Abstract

Insulin-sensitive lipogenesis dominates the body lipid deposition; however, nonalcoholic fatty liver disease (NAFLD) develops in the insulin-resistant state. The regulation mechanism of Insulin resistance-driven NAFLD remains elusive. Using zebrafish model of Insulin resistance (ZIR, insrb-/-) and mouse hepatocytes (NCTC 1469), we explored the regulation mechanism of Insulin resistance-driven hepatic lipid deposition under the stimulation of carbohydrate diet (CHD). In ZIR model, Insulin resistance induced hyperlipidemia and elevated hepatic lipid deposition via elevating the gene/protein expressions of lipogenic enzymes, that was activated by carbohydrate response element binding protein (ChREBP), rather than sterol regulatory element binding proteins 1c (SREBP-1c). The metabolomic analysis in zebrafish and silencing of chrebp in mouse hepatocytes revealed that the increased hepatic frucotose-6-phosphate (F6P) and glucose-6-phosphate (G6P) promoted the ChREBP-mediated lipid deposition. We further identified that F6P alone was sufficient to activate ChREBP-mediated lipid deposition by a SREBP-1c-independent manner. Moreover, we clarified the suppressed hepatic phosphofructokinase/glucose-6-phosphatase functions and the normal Glucokinase function preserved by glucose transporter 2 (GLUT2) manipulated the increased F6P/G6P content in ZIR. In conclusion, the present study revealed that Insulin resistance promoted hepatic lipid deposition via the F6P/G6P-mediated ChREBP activation. Our findings deciphered the main regulation pathway for the liver lipid deposition in the insulin-resistant state and identified F6P as a new potential regulator for ChREBP.

Keywords

ChREBP; Frucotose-6-phosphate; Insulin resistance; Lipid metabolism.

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