title: Endoplasmic Reticulum Lipid Flux Influences Enterocyte Nuclear Morphology and Lipid-dependent Transcriptional Responses.
abstract: 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 of 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 RNA sequencing, revealing a cohort of up-regulated genes associated with lipid droplet formation and lipid transport via lipoprotein particles. Using a microsomal triglyceride transfer protein (MTP) inhibitor to block β-lipoprotein particle formation, we demonstrate that the transcriptional response to a high-fat meal is associated with the transfer of ER triglyceride to nascent β-lipoproteins, possibly through the activation of Creb3l3/cyclic AMP-responsive element-binding protein. 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.
authors.affiliation: From the Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218 and.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Zeituni
authors.affiliation: From the Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218 and.
authors.forename: Meredith H
authors.initials: MH
authors.lastname: Wilson
authors.affiliation: From the Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218 and.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: the Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Iglesias
authors.affiliation: From the Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218 and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sepanski
authors.affiliation: From the Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218 and.
authors.forename: Mahmud A
authors.initials: MA
authors.lastname: Siddiqi
authors.affiliation: From the Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218 and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Anderson
authors.affiliation: From the Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218 and.
authors.forename: Yixian
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: From the Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218 and farber@ciwemb.edu.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Farber
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D066292:Lipid Droplets / Q000378:metabolism; D050356:Lipid Metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D014280:Triglycerides; D029961:Zebrafish Proteins
keywords: apoA-IV; creb3l3; enterocyte; intestine; lipid droplet; lipoprotein; mitochondria; nucleus; plin2