PUBLICATION
Biosynthetic deficiency of docosahexaenoic acid causes nonalcoholic fatty liver disease and ferroptosis-mediated hepatocyte injury
- Authors
- Li, X., Liu, C., Zhang, R., Li, Y., Ye, D., Wang, H., He, M., Sun, Y.
- ID
- ZDB-PUB-240525-14
- Date
- 2024
- Source
- The Journal of biological chemistry 300(7): 107405 (Journal)
- Registered Authors
- He, Mudan, Sun, Yonghua, Ye, Ding
- Keywords
- docosahexaenoic acid, elovl2, fatty liver, ferroptosis, lipid homeostasis
- MeSH Terms
-
- Animals
- Docosahexaenoic Acids*/biosynthesis
- Docosahexaenoic Acids*/metabolism
- Endoplasmic Reticulum Stress
- Ferroptosis*
- Hepatocytes*/metabolism
- Hepatocytes*/pathology
- Lipid Metabolism
- Mutation
- Non-alcoholic Fatty Liver Disease*/genetics
- Non-alcoholic Fatty Liver Disease*/metabolism
- Non-alcoholic Fatty Liver Disease*/pathology
- Zebrafish*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 38788853 Full text @ J. Biol. Chem.
Citation
Li, X., Liu, C., Zhang, R., Li, Y., Ye, D., Wang, H., He, M., Sun, Y. (2024) Biosynthetic deficiency of docosahexaenoic acid causes nonalcoholic fatty liver disease and ferroptosis-mediated hepatocyte injury. The Journal of biological chemistry. 300(7):107405.
Abstract
Exogenous omega-3 fatty acids, particularly docosahexaenoic acid (DHA), have shown to exert beneficial effects on nonalcoholic fatty liver disease (NAFLD), which is characterized by the excessive accumulation of lipids and chronic injury in the liver. However, the effect of endogenous DHA biosynthesis on the lipid homeostasis of liver is poorly understood. In this study, we used a DHA biosynthesis-deficient zebrafish model, elovl2 mutant, to explore the effect of endogenously biosynthesized DHA on hepatic lipid homeostasis. We found the pathways of lipogenesis and lipid uptake were strongly activated, while the pathways of lipid oxidation and lipid transport were inhibited in the liver of elovl2 mutants, leading to lipid droplet accumulation in the mutant hepatocytes and NAFLD. Furthermore, the elovl2 mutant hepatocytes exhibited disrupted mitochondrial structure and function, activated endoplasmic reticulum (ER) stress, and hepatic injury. We further unveiled that the hepatic cell death and injury was mainly mediated by ferroptosis, rather than apoptosis, in elovl2 mutants. Elevating DHA content in elovl2 mutants, either through introduction of an omega-3 desaturase (fat1) transgene or feeding with a DHA-rich diet, could strongly alleviate NAFLD features and ferroptosis-mediated hepatic injury. Together, our study elucidates the essential role of endogenous DHA biosynthesis in maintaining hepatic lipid homeostasis and liver health, highlighting that DHA deficiency can lead to NAFLD and ferroptosis-mediated hepatic injury.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping