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.
Highlights
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)
The intestine is potentially an important regulating organ for systemic lipid metabolism, instead of solely a port of entry. It has been shown in other cell types, including murine fibroblasts and adipocytes, that DGAT1 is involved in the Abbreviations: CHOP, C/EBP homologous protein; CM, chylomicron; DG, diacylglycerol; DGAT, diacylglycerol acyltransferase; DGAT1 inhibitor (D1i), diacylglycerol acyltransferase 1 inhibitor; DGAT2 inhibitor (D2i), diacylglycerol acyltransferase 2 inhibitor; DGAT2 overexpressing (D2OE), DGAT2 overexpression; DM, differentiation medium; EM, expansion medium; HFD, high-fat diet; IRE1, inositol requiring enzyme 1; LC50, concentration resulting in half-maximal cell lethality; LD, lipid droplet; MFI, mean fluorescent intensity; OA, oleic acid; PA, palmitic acid; protein kinaselike ER kinase (PERK), RNA-activated protein kinase-like ER kinase; PI, propidium iodide; PLE, protein losing enteropathy; SFA, saturated FA; SSC-A, side scatter area; TG, triglyceride/triacylglycerol; UFA, unsaturated FA; UPR, unfolded protein response; XBP1, X-box binding protein 1
We found that D2i treatment in DGAT1-deficient organoids completely abolished LD formation, whereas LD formation in control organoids was not affected by inhibition of DGAT2 (Fig. 1A)
Summary
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). The intestine is potentially an important regulating organ for systemic lipid metabolism, instead of solely a port of entry It has been shown in other cell types, including murine fibroblasts and adipocytes, that DGAT1 is involved in the Abbreviations: CHOP, C/EBP homologous protein; CM, chylomicron; DG, diacylglycerol; DGAT, diacylglycerol acyltransferase; D1i, diacylglycerol acyltransferase 1 inhibitor; D2i, diacylglycerol acyltransferase 2 inhibitor; D2OE, DGAT2 overexpression; DM, differentiation medium; EM, expansion medium; HFD, high-fat diet; IRE1, inositol requiring enzyme 1; LC50, concentration resulting in half-maximal cell lethality; LD, lipid droplet; MFI, mean fluorescent intensity; OA, oleic acid; PA, palmitic acid; PERK, RNA-activated protein kinase-like ER kinase; PI, propidium iodide; PLE, protein losing enteropathy; SFA, saturated FA; SSC-A, side scatter area; TG, triglyceride/triacylglycerol; UFA, unsaturated FA; UPR, unfolded protein response; XBP1, X-box binding protein 1
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