Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice
Leukotrienes are potent mediators of the inflammatory response and 5-lipoxygenase, the enzyme responsible for their synthesis, is dependent on its interaction with 5-lipoxygenase activating protein for optimum catalysis. Previous studies had demonstrated that macrophage infiltration into adipose tis...
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Elsevier
2024-01-01
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| Series: | Current Research in Pharmacology and Drug Discovery |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590257124000300 |
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| author | Katherine Keever Bardia Askari |
| author_facet | Katherine Keever Bardia Askari |
| author_sort | Katherine Keever |
| collection | DOAJ |
| description | Leukotrienes are potent mediators of the inflammatory response and 5-lipoxygenase, the enzyme responsible for their synthesis, is dependent on its interaction with 5-lipoxygenase activating protein for optimum catalysis. Previous studies had demonstrated that macrophage infiltration into adipose tissue is associated with obesity and atherosclerosis in LDLR−/− mice fed a high fat-high carbohydrate. The present study was undertaken to determine whether inhibition of 5-lipoxygenase activating protein is efficacious in attenuating adipose tissue inflammation in LDLR−/− mice fed a high fat-high carbohydrate. 10-week old male LDLR−/− mice were fed a high fat-high carbohydrate diet for 22-weeks, with or without MK886 (40 mg/kg/day, ad libitum) a well-established 5-lipoxygenase activating protein inhibitor. All mice had an approximate 2-fold increase in total body weight, but a 6-week course of MK886 treatment had differential effects on adipose tissue size, without affecting macrophage accumulation. MK886 exacerbated the dyslipidemia, increased serum amyloid A content of high-density lipoproteins and caused a profound hepatomegaly. Dyslipidemia and increased serum amyloid A were concomitant with increases in atherosclerosis. In conclusion, MK886 paradoxically exacerbated hyperlipidemia and the pro-inflammatory phenotype in a mouse model of diet-induced atherosclerosis, possibly via a disruption of hepatic lipid metabolism and increased inflammation. |
| format | Article |
| id | doaj-art-6276834b4e824a93b7fcfcaea927f505 |
| institution | OA Journals |
| issn | 2590-2571 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
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| series | Current Research in Pharmacology and Drug Discovery |
| spelling | doaj-art-6276834b4e824a93b7fcfcaea927f5052025-08-20T01:56:34ZengElsevierCurrent Research in Pharmacology and Drug Discovery2590-25712024-01-01710020310.1016/j.crphar.2024.100203Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic miceKatherine Keever0Bardia Askari1Department of Biomedical Sciences, New York Institute of Technology-College of Osteopathic Medicine, Old Westbury, NY, USADepartment of Biomedical Sciences, New York Institute of Technology-College of Osteopathic Medicine, Old Westbury, NY, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Corresponding author. Department of Biomedical Sciences, New York Institute of Technology-College of Osteopathic Medicine, Old Westbury, NY, USA.Leukotrienes are potent mediators of the inflammatory response and 5-lipoxygenase, the enzyme responsible for their synthesis, is dependent on its interaction with 5-lipoxygenase activating protein for optimum catalysis. Previous studies had demonstrated that macrophage infiltration into adipose tissue is associated with obesity and atherosclerosis in LDLR−/− mice fed a high fat-high carbohydrate. The present study was undertaken to determine whether inhibition of 5-lipoxygenase activating protein is efficacious in attenuating adipose tissue inflammation in LDLR−/− mice fed a high fat-high carbohydrate. 10-week old male LDLR−/− mice were fed a high fat-high carbohydrate diet for 22-weeks, with or without MK886 (40 mg/kg/day, ad libitum) a well-established 5-lipoxygenase activating protein inhibitor. All mice had an approximate 2-fold increase in total body weight, but a 6-week course of MK886 treatment had differential effects on adipose tissue size, without affecting macrophage accumulation. MK886 exacerbated the dyslipidemia, increased serum amyloid A content of high-density lipoproteins and caused a profound hepatomegaly. Dyslipidemia and increased serum amyloid A were concomitant with increases in atherosclerosis. In conclusion, MK886 paradoxically exacerbated hyperlipidemia and the pro-inflammatory phenotype in a mouse model of diet-induced atherosclerosis, possibly via a disruption of hepatic lipid metabolism and increased inflammation.http://www.sciencedirect.com/science/article/pii/S2590257124000300AtherosclerosisAdipose tissueInflammationPPARαFLAPSteatosis |
| spellingShingle | Katherine Keever Bardia Askari Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice Current Research in Pharmacology and Drug Discovery Atherosclerosis Adipose tissue Inflammation PPARα FLAP Steatosis |
| title | Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice |
| title_full | Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice |
| title_fullStr | Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice |
| title_full_unstemmed | Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice |
| title_short | Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice |
| title_sort | exacerbation of atherosclerosis hyperlipidemia and inflammation by mk886 an inhibitor of leukotriene biosynthesis in obese and diabetic mice |
| topic | Atherosclerosis Adipose tissue Inflammation PPARα FLAP Steatosis |
| url | http://www.sciencedirect.com/science/article/pii/S2590257124000300 |
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