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
  • 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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