PUBLICATION
Creb3l3 deficiency promotes intestinal lipid accumulation and alters ApoB-containing lipoprotein kinetics
- Authors
- Sweeney, D.W., Shen, M.C., Farber, S.A.
- ID
- ZDB-PUB-250601-10
- Date
- 2025
- Source
- Journal of Lipid Research : 100833100833 (Journal)
- Registered Authors
- Farber, Steven
- Keywords
- CREB3L3, CREBH, chylomicron, enterocyte, lipid, zebrafish
- MeSH Terms
-
- Intestinal Mucosa*/metabolism
- Apolipoproteins B*/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- Cyclic AMP Response Element-Binding Protein*/deficiency
- Cyclic AMP Response Element-Binding Protein*/genetics
- Cyclic AMP Response Element-Binding Protein*/metabolism
- Zebrafish Proteins*/deficiency
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Animals
- Lipid Metabolism*
- PubMed
- 40449732 Full text @ J. Lipid Res.
Citation
Sweeney, D.W., Shen, M.C., Farber, S.A. (2025) Creb3l3 deficiency promotes intestinal lipid accumulation and alters ApoB-containing lipoprotein kinetics. Journal of Lipid Research. :100833100833.
Abstract
Elevated levels of triglycerides in the bloodstream, a condition known as hypertriglyceridemia, represent a significant risk factor for the development of metabolic disorders and cardiovascular diseases. One key regulator of lipid metabolism is the transcription factor Creb3l3, which is expressed in the liver, intestine, and adipose tissue. Creb3l3 is localized to the endoplasmic reticulum (ER) membrane, and in vertebrates plays a crucial role in plasma lipid homeostasis. However, the precise molecular mechanisms underlying Creb3l3's influence on cellular lipid metabolism remains undefined. To address this knowledge gap, we generated zebrafish mutants lacking both creb3l3 orthologs (creb3l3a and creb3l3b). Gene expression analysis revealed that key creb3l3 target genes, such as apoC2 and apoA4, were significantly downregulated in the intestines of these double mutants. Using two zebrafish lipoprotein reporter lines we assessed lipoprotein dynamics in creb3l3 mutants. Despite producing similar total levels of lipoproteins, creb3l3 mutants exhibited impaired lipoprotein turnover, suggesting a disruption in circulating lipid clearance. Additionally, histological analysis showed an accumulation of intestinal lipids, characterized by an increased number and size of enterocyte lipid droplets. These findings indicate that creb3l3 is essential for regulating postprandial lipid flux in enterocytes through altering the balance between lipid storage and secretion. Our study highlights a critical unappreciated role of Creb3l3 in maintaining intestinal lipid homeostasis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping