PUBLICATION
F6P/G6P-mediated ChREBP activation promotes the insulin resistance-driven hepatic lipid deposition in zebrafish
- Authors
- Gong, Y., Lu, Q., Xi, L., Liu, Y., Yang, B., Su, J., Liu, H., Jin, J., Zhang, Z., Yang, Y., Zhu, X., Xie, S., Han, D.
- ID
- ZDB-PUB-231002-115
- Date
- 2023
- Source
- The Journal of Nutritional Biochemistry 122: 109452 (Journal)
- Registered Authors
- Han, Dong, Xie, Shouqi, Zhu, Xiaoming
- Keywords
- ChREBP, Frucotose-6-phosphate, Insulin resistance, Lipid metabolism
- MeSH Terms
-
- Animals
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
- Carbohydrates
- Insulin/metabolism
- Insulin Resistance*/physiology
- Lipids
- Lipogenesis
- Liver/metabolism
- Mice
- Non-alcoholic Fatty Liver Disease*/etiology
- Non-alcoholic Fatty Liver Disease*/metabolism
- Phosphates/metabolism
- Proteins/metabolism
- Sterol Regulatory Element Binding Protein 1/genetics
- Sterol Regulatory Element Binding Protein 1/metabolism
- Zebrafish/metabolism
- PubMed
- 37748621 Full text @ J. Nutr. Biochem.
Citation
Gong, Y., Lu, Q., Xi, L., Liu, Y., Yang, B., Su, J., Liu, H., Jin, J., Zhang, Z., Yang, Y., Zhu, X., Xie, S., Han, D. (2023) F6P/G6P-mediated ChREBP activation promotes the insulin resistance-driven hepatic lipid deposition in zebrafish. The Journal of Nutritional Biochemistry. 122:109452.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping