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

Abstract

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Lipid Droplets in Lung Cancers Are Crucial for the Cell Growth and Starvation Survival

“…Although the depletion of LDs is not harmful to these cells under normal condition, this treatment might contribute to a slowdown of lung cancer progression. While a two- to three- day simultaneous treatment of DGAT1 and DGAT2 inhibitors administered twice daily to mice immediately after a 4-week high-fat diet could significantly decrease intestinal TG secretion into the blood circulatory system [ 31 ], severe watery diarrhea and sporadic death after this treatment could hinder the pursuit of slowing down lung cancer progression by DGAT inhibition. Adjustment of the regimen to simultaneous administration of the two inhibitors to mice once daily (3 mg/kg PF-04620110 and 7.5 mg/kg PF-06424439) with an ad libitum normal diet for 7 days could significantly reduce the plasma TG level 4 h after drug administration.…”

Basal re-esterification finetunes mitochondrial fatty acid utilization

“…www.molecularmetabolism.com DGAT1 in esterifying the majority of lipolysis-derived FAs, there seems to be some specialization of the function of DGAT1 and 2 possibly in a species and tissue-dependent manner [8,10e12,22,33]. DGAT1 lossof-function mutation in humans causes severe diarrhea [46] but a global Dgat1 knockout or pharmacological inhibition of DGAT1 in mice does not exhibit a similar phenotype [14,18,35], while, a combined DGAT inhibition in mice causes diarrhea-like symptoms [15]. Thus, it seems that intestinal absorption in humans depends on DGAT1, while in mice DGAT2 can in part replace intestinal DGAT1 action.…”

“…We thus argue that only a combined inhibition (D1þ2i) can reveal the true role of re-esterification in energy homeostasis. To avoid adaptive response to gene knockdown or knockout, we used specific pharmacological inhibitors of DGAT1 (PF-04,620,110, D1i) and DGAT2 (PF-06,424,439, D2i) [6,8,15,16,23] for combined DGAT inhibition (D1þ2i) in murine adipocytes. We show that D1þ2i results in a substantial increase in oxygen consumption caused by lipolysis derived FAs.…”

Dynamic changes in intestinal microbiota and metabolite composition of pre-weaned beef calves

“…When the intestinal ora is in a healthy state, the body maintains an environment suitable for nutrient metabolite absorption. However, disordered intestinal ora impairs the function of the intestinal barrier, which weakens the absorption of FAs by intestinal epithelial cells and leads to loss of large amounts of FAs [74]. Therefore, high FA concentrations in the intestine lead to an imbalance in host metabolic homeostasis and weakened disease resistance.…”