ABSTRACT
BACKGROUND: Chronic inflammation has been linked to insulin resistance and type 2 diabetes mellitus (T2DM). High-fat diet (HFD)-derived fatty acid is associated with the activation of chronic inflammation in T2DM. PF-04620110, which is currently in phase 1 clinical trials as a selective acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) inhibitor, is a potent anti-diabetic agent that may be important for the regulation of chronic inflammation in T2DM. However, the mechanisms by which PF-04620110 regulates fatty acid-induced chronic inflammation remain unclear. METHODS: PF-04620110 was used in vitro and in vivo. DGAT1-targeting gRNAs were used for deletion of mouse DGAT1 via CRISPR ribonucleoprotein (RNP) system. The activation of NLRP3 inflammasome was measured by immunoblot or cytokine analysis in vitro and in vivo. RESULTS: Here we show that PF-04620110 suppressed fatty acid-induced nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome activation in macrophages. In contrast, PF-04620110 did not change the activation of the NLR family, CARD-domain-containing 4 (NLRC4), or the absent in melanoma 2 (AIM2) inflammasomes. Moreover, PF-04620110 inhibited K⁺ efflux and the NLRP3 inflammasome complex formation, which are required for NLRP3 inflammasome activation. PF-04620110 reduced the production of interleukin 1β (IL-1β) and IL-18 and blood glucose levels in the plasma of mice fed HFD. Furthermore, genetic inhibition of DGAT1 suppressed fatty acid-induced NLRP3 inflammasome activation. CONCLUSION: Our results suggest that PF-04620110 suppresses fatty acid-induced NLRP3 inflammasome activation.
Subject(s)
Animals , Humans , Mice , Blood Glucose , Clinical Trials, Phase I as Topic , Clustered Regularly Interspaced Short Palindromic Repeats , Diabetes Mellitus, Type 2 , Diacylglycerol O-Acyltransferase , Diet, High-Fat , Fatty Acids , In Vitro Techniques , Inflammasomes , Inflammation , Insulin Resistance , Interleukin-18 , Interleukins , Macrophages , Melanoma , Plasma , RibonucleoproteinsABSTRACT
This study was designed to analyze the prevalence rates of laboratory animal allergy (LAA) in laboratory workers who perform researches with animals, and detect the mouse urinary allergen (Mus m 1) level in animal facilities for the purpose of establishing program for prevention of exposure to allergen. Study subjects were 240 employees who were working for two animal research institutions in Korea. Then the questionnaire and skin prick tests (SPTs) using twenty allergens were conducted with them. Presence of Mus m 1 in each air borne sample collected from animal facility was determined by using enzyme-linked immunosorbent assay. Through 240 questionnaire sheets, we found that; (1) 17.0% of workers in the direct exposure group answered that they had allergic symptoms due to laboratory animals; and (2) 6.2% of them had asthmatic symptoms. Twenty one subjects (27.6%) among the subjects with common allergens positive result and five subjects (6.6%) among the subjects with negative result showed a positive response to LAA under the SPTs. The Mus m 1 concentration (1.339 ng/m3) in the sample collected during cage exchange in mouse breeding room was up to 2.8 times higher than its concentration (0.483 ng/m3) in the sample collected at the stationary state. We suggest that LAA management programs including control of exposure to laboratory animal allergens should be considered as a measure to reduce the incidence of LAA and relieve the laboratory worker's allergic sensitivity to laboratory animals.