Endoplasmic reticulum lipid flux influences enterocyte nuclear morphology and lipid-dependent transcriptional responses
- Zeituni, E.M., Wilson, M.H., Zheng, X., Iglesias, P.A., Sepanski, M., Siddiqi, M.A., Anderson, J.L., Zheng, Y., Farber, S.A.
- The Journal of biological chemistry 291(45): 23804-23816 (Journal)
- Registered Authors
- Anderson, Jennifer, Farber, Steven
- ApoA-IV, creb3l3, enterocyte, intestine, lipid droplet, lipoprotein, mitochondria, nucleus, plin2
- MeSH Terms
- Cyclic AMP Response Element-Binding Protein/genetics
- Cyclic AMP Response Element-Binding Protein/metabolism
- Diet, High-Fat*/adverse effects
- Endoplasmic Reticulum/genetics
- Endoplasmic Reticulum/metabolism*
- Lipid Droplets/metabolism
- Lipid Metabolism*
- Transcriptional Activation*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- 27655916 Full text @ J. Biol. Chem.
Zeituni, E.M., Wilson, M.H., Zheng, X., Iglesias, P.A., Sepanski, M., Siddiqi, M.A., Anderson, J.L., Zheng, Y., Farber, S.A. (2016) Endoplasmic reticulum lipid flux influences enterocyte nuclear morphology and lipid-dependent transcriptional responses. The Journal of biological chemistry. 291(45):23804-23816.
Responding to a high-fat meal requires an interplay between multiple digestive tissues, sympathetic response pathways, and the gut microbiome. The epithelial enterocytes of the intestine are responsible for absorbing dietary nutrients and preparing them for circulation to distal tissues, which requires significant changes in cellular activity, including both morphological and transcriptional responses. Following a high-fat meal, we observe morphological changes in the enterocytes larval zebrafish, including elongation of mitochondria, formation and expansion of lipid droplets, and the rapid and transient ruffling of the nuclear periphery. Dietary and pharmacological manipulation of zebrafish larvae demonstrated that these subcellular changes are specific to triglyceride absorption. The transcriptional changes that occur simultaneously with these morphological changes were determined using RNASeq revealing a cohort of up-regulated genes associated with lipid droplet formation and lipid transport via lipoprotein particles. Using an Mtp inhibitor to block beta-lipoprotein particle formation, we demonstrate that the transcriptional response to a high-fat meal is associated with the transfer of ER triglyceride to nascent beta-lipoproteins, possibly through the activation of Creb3l3 (Crebh). These data suggest that a transient increase in ER lipids is the likely mediator of the initial physiological response of intestinal enterocytes to dietary lipid.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes