Reversible deficits in apical transporter trafficking associated with deficiency in diacylglycerol acyltransferase
Year: 2018
Type: article
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.
Source: Traffic
DOI: 10.1111/tra.12608
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: bronze
Funders: U.S. Department of Veterans Affairs, Vanderbilt University, Vanderbilt Institute for Clinical and Translational Research, Vanderbilt-Ingram Cancer Center, National Institutes of Health, National Eye Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G107554336, G1149166549, G1300984159, G1421574136, G1764958080, G1845105935, G2274310868, G2596855291, G2635992203, G2699569218, G275963511, G2940777275, G2986679874, G3048723701, G3051419658, G3078270764, Vanderbilt Mouse Metabolic Phenotyping Center, G3433274139, G344109072, G3577298753, G3722609264, G3726302789, G3728103286, Molecular characteristics of the apical recycling system, G3756376927, Conducting Child Health Care Research in Vulnerable Populations, G3865556588, G3989539122, G4020890471, Vanderbilt Mouse Metabolic Phenotyping Center, G410019888, G4181736377, G4226733505, G4320917349, G4348242538, G4513176822, G5580019600, G5671168073, G5719746234, G572144156, G5853943267, G6524276951, G6546324823, G6569741389, G659731888, G6648494404, G6922361213, G7038757410, G7220527126, G8099314058, G8342124450, Training in Gastroenterology, Molecular and Cellular Basis for Digestive Diseases, Vanderbilt Institute for Clinical and Translational Research (VICTR), Cancer Center Support Grant, Surgical Oncology Training Grant, Vanderbilt Diabetes Research Center, Small GTP Binding Proteins in Gastrointestinal Mucosa, Core Grant in Vision Research
OpenAlex ID: W2885104726