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Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice.

ABSTRACT: The intestinal metabolism and transport of triacylglycerol (TAG) play a critical role in dietary TAG absorption, and defects in the process are associated with congenital diarrhea. The final reaction in TAG synthesis is catalyzed by diacylglycerol acyltransferase (DGAT1 and DGAT2), which uses activated fatty acids (FA) as substrates. Loss-of-function mutations in DGAT1 cause watery diarrhea in humans, but mechanisms underlying the relationship between altered DGAT activity and diarrhea remain largely unclear. Here, the effects of DGAT1 and DGAT2 inhibition, alone or in combination, on dietary TAG absorption and diarrhea in mice were investigated by using a selective DGAT1 inhibitor (PF-04620110) and DGAT2 inhibitor (PF-06424439). Simultaneous administration of a single dosing of these inhibitors drastically decreased intestinal TAG secretion into the blood circulatory system and TAG accumulation in the duodenum at 60 min after lipid gavage. Under 60% high-fat diet (HFD) feeding, their repeated simultaneous administration for 2 days induced severe watery diarrhea and occasionally led to death. The diarrhea was accompanied by enhanced fecal FA excretion, intestinal injury and barrier failure. DGAT1 or DGAT2 inhibition alone did not induce the phenotypic changes observed in DGAT1/2 inhibitor-treated mice. The results demonstrate that DGAT1/2 inhibition alters TAG absorption and results in watery diarrhea in mice. DGAT1/2 inhibition-induced diarrhea may be caused by intestinal barrier dysfunction due to dysregulation of the cytotoxic FA metabolism. These findings suggest that DGAT-mediated intestinal TAG synthesis is a vital step for maintaining intestinal barrier integrity under HFD feeding.

SUBMITTER: Takemoto K

PROVIDER: S-EPMC7422801 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice.

Takemoto Kosuke K Fukasaka Yumiko Y Yoshimoto Ryo R Nambu Hirohide H Yukioka Hideo H

Physiological reports 20200801 15

The intestinal metabolism and transport of triacylglycerol (TAG) play a critical role in dietary TAG absorption, and defects in the process are associated with congenital diarrhea. The final reaction in TAG synthesis is catalyzed by diacylglycerol acyltransferase (DGAT1 and DGAT2), which uses activated fatty acids (FA) as substrates. Loss-of-function mutations in DGAT1 cause watery diarrhea in humans, but mechanisms underlying the relationship between altered DGAT activity and diarrhea remain la ...[more]

PMID: 32786057

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Project description:(1) Background: Nutritional strategies to enhance gut function and reduce the piglet diarrhea rate are critical to increase the growth performance of piglets. The purpose of this study was to investigate whether dietary fat types and/or fat microencapsulation techniques are involved in regulating the fatty acid transport system and the mechanical and immunological barriers of the small intestine. (2) Methods: Three hundred twenty-four weaning piglets were randomly divided into three groups fed a soybean oil diet (SBO, control group, 6.0% soybean oil), palm oil diet (PO, 6.0% palm oil), or encapsulated palm oil diet (EPO, 7.5% encapsulated palm oil). (3) Results: A significantly lower mRNA expression of the claudin was observed in the duodenum and jejunum of the PO group than in the SBO group (p < 0.05). However, the mRNA expression and protein abundance of claudin and ZO-1 in the jejunum of the EPO group were higher (p < 0.05) than in the PO group. Porcine β-defensin (pBD) secretion was not significantly different between the SBO and PO groups (p > 0.05), while the pBD-2 levels were significantly different (p < 0.05). Compared with the PO group, the EPO group exhibited a significantly increased secretion of pBD-2 and pBD-129 in the small intestine (p < 0.05) and pBD-1 in the jejunum and ileum (p < 0.05). The protein abundances of apolipoprotein AIV (Apo AIV) and intestinal fatty acid binding protein (I-FABP) were significantly lower in the PO group than in the SBO group (p < 0.05). Simultaneously, the protein abundances of fatty acid transport protein 4 (FATP4), fatty acid translocase (CD36), and I-FABP were higher in the EPO group than in the PO group. Furthermore, the low digestibility of palm oil (PO group) might negatively regulate intestinal tight junctions, fatty acid transporters, lipoproteins, and β-defensin through the activation of the AMPK/mTORC1 and AMPK/Sirt1/NF-κB pathways. (4) Conclusions: In summary, microencapsulation techniques might alleviate the negative effects of palm oil and help to improve the intestinal fatty acid transport system and barrier function.

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Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice.

Publications

Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice.

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