@article{9124a6ed4148497f9af9b7051c5e8b14,
title = "Reversible deficits in apical transporter trafficking associated with deficiency in diacylglycerol acyltransferase",
abstract = "Deficiency in diacylglycerol acyltransferase (DGAT1) is a rare cause of neonatal diarrhea, without a known mechanism or in vitro model. A patient presenting at our institution at 7 weeks of life with failure to thrive and diarrhea was found by whole-exome sequencing to have a homozygous DGAT1 truncation mutation. Duodenal biopsies showed loss of DGAT1 and deficits in apical membrane transporters and junctional proteins in enterocytes. When placed on a very low-fat diet, the patient's diarrhea resolved with normalization of brush border transporter localization in endoscopic biopsies. DGAT1 knockdown in Caco2-BBe cells modeled the deficits in apical trafficking, with loss of apical DPPIV and junctional occludin. Elevation in cellular lipid levels, including diacylglycerol (DAG) and phospholipid metabolites of DAG, was documented by lipid analysis in DGAT1 knockdown cells. Culture of the DGAT1 knockdown cells in lipid-depleted media led to re-establishment of occludin and return of apical DPPIV. DGAT1 loss appears to elicit global changes in enterocyte polarized trafficking that could account for deficits in absorption seen in the patient. The in vitro modeling of this disease should allow for investigation of possible therapeutic targets.",
keywords = "CLDN4, Caco2, DGAT1, JAM, Rab11a, diarrhea, enterocyte, intestine, occludin",
author = "Cameron Schlegel and Lapierre, {Lynne A.} and Weis, {Victoria G.} and Williams, {Janice A.} and Izumi Kaji and Carolina Pinzon-Guzman and Nripesh Prasad and Braden Boone and Angela Jones and Hernan Correa and Levy, {Shawn E.} and Xianlin Han and Miao Wang and Kelly Thomsen and Sari Acra and Goldenring, {James R.}",
note = "Funding Information: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Grant/ Award Number: T32 HD060554 ; National Cancer Institute, Grant/Award Number: T32 CA106183; National Center for Advancing Translational Sciences, Grant/Award Number: UL1 TR002243; National Institute of Diabetes and Digestive and Kidney Diseases, Grant/ Award Number: P30 DK058404R01 DK48370 R01 DK70856 T32 DK007673 Funding Information: information Eunice Kennedy Shriver National Institute of Child Health and Human Development, Grant/Award Number: T32 HD060554; National Cancer Institute, Grant/Award Number: T32 CA106183; National Center for Advancing Translational Sciences, Grant/Award Number: UL1 TR002243; National Institute of Diabetes and Digestive and Kidney Diseases, Grant/Award Number: P30 DK058404R01 DK48370 R01 DK70856 T32 DK007673This work was supported by the National Institute of Health (NIH) grants R01 DK48370 and R01 DK70856 to JRG and a gift from the Christine Volpe Fund and a Pilot Translational Research Award to SA and JRG funded by the Vanderbilt Digestive Disease Center (P30 DK058404) and the Vanderbilt Institute for Clinical and Translational Research (UL1 TR002243). CS and VGW were supported by T32 HD060554 and T32 DK007673. CP-Z was supported by T32 CA106183. This work was supported by core resources of the Vanderbilt Digestive Disease Center, (P30 DK058404) the Vanderbilt-Ingram Cancer Center (P30 CA68485), and imaging supported by both the Vanderbilt Combined Imaging Shared Resource (CA68485, DK20593, DK58404, DK59637, EY08126) and the Vanderbilt Digital Histology Shared Resource, supported by VA Shared Instrumentation Grant (1IS1BX003097). The Editorial Process File is available in the online version of this article. Funding Information: This work was supported by the National Institute of Health (NIH) grants R01 DK48370 and R01 DK70856 to JRG and a gift from the Christine Volpe Fund and a Pilot Translational Research Award to SA and JRG funded by the Vanderbilt Digestive Disease Center (P30 DK058404) and the Vanderbilt Institute for Clinical and Translational Research (UL1 TR002243). CS and VGW were supported by T32 HD060554 and T32 DK007673. CP-Z was supported by T32 CA106183. This work was supported by core resources of the Vanderbilt Digestive Disease Center, (P30 DK058404) the Vanderbilt-Ingram Cancer Center (P30 CA68485), and imaging supported by both the Vanderbilt Combined Imaging Shared Resource (CA68485, DK20593, DK58404, DK59637, EY08126) and the Vanderbilt Digital Histology Shared Resource, supported by VA Shared Instrumentation Grant (1IS1BX003097). Publisher Copyright: {\textcopyright} 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd",
year = "2018",
month = nov,
doi = "10.1111/tra.12608",
language = "English (US)",
volume = "19",
pages = "879--892",
journal = "Traffic",
issn = "1398-9219",
publisher = "Blackwell Munksgaard",
number = "11",
}