DGAT2 partially compensates for lipid-induced ER stress in human DGAT1-deficient intestinal stem cells[S]

Jorik M van Rijn, Marliek van Hoesel, Cecilia de Heus, Anke H M van Vugt, Judith Klumperman, Edward Nieuwenhuis, Roderick H J Houwen, Sabine Middendorp

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Dietary lipids are taken up as FAs by the intestinal epithelium and converted by diacylglycerol acyltransferase (DGAT) enzymes into triglycerides, which are packaged in chylomicrons or stored in cytoplasmic lipid droplets (LDs). DGAT1-deficient patients suffer from vomiting, diarrhea, and protein losing enteropathy, illustrating the importance of this process to intestinal homeostasis. Previously, we have shown that DGAT1 deficiency causes decreased LD formation and resistance to unsaturated FA lipotoxicity in patient-derived intestinal organoids. However, LD formation was not completely abolished in patient-derived organoids, suggesting the presence of an alternative mechanism for LD formation. Here, we show an unexpected role for DGAT2 in lipid metabolism, as DGAT2 partially compensates for LD formation and lipotoxicity in DGAT1-deficient intestinal stem cells. Furthermore, we show that (un)saturated FA-induced lipotoxicity is mediated by ER stress. More importantly, we demonstrate that overexpression of DGAT2 fully compensates for the loss of DGAT1 in organoids, indicating that induced DGAT2 expression in patient cells may serve as a therapeutic target in the future.

Original languageEnglish
Pages (from-to)1787-1800
Number of pages14
JournalJournal of Lipid Research
Volume60
Issue number10
Early online date17 Jul 2019
DOIs
Publication statusPublished - Oct 2019

Keywords

  • Diacylglycerol acyltransferase 1
  • Diacylglycerol acyltransferase 2
  • Diet and dietary lipids
  • Diseases
  • Fatty acid
  • Intestine
  • Lipid droplets
  • Lipotoxicity
  • Triglycerides

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