Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fenofibrate and rosiglitazone are prescribed to treat hypertriglyceridemia and diabetes, respectively. Since fenofibrate improves lipid profile in diabetic patients and improves insulin resistance in animal models, we examined the mechanism of antidiabetic effects of fenofibrate in KKAy mouse, an animal model of diabetes and dyslipidemia. KKAy mice were treated with fenofibrate, rosiglitazone, liver x receptor agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317), and a combination of fenofibrate and T090317 for 2 weeks. Fenofibrate lowered serum triglycerides by 90% and free fatty acid (FFA) by 50% via inhibition of hepatic fatty acid synthesis. Fenofibrate also prevented T0901317-induced increases of triglycerides by dampening T090317-mediated sterol response element binding protein 1c (SREBP1c) up-regulation. Glucose lowering was comparable (approximately 40%) in fenofibrate and rosiglitazone treated mice. T090317 also showed mild reduction in serum glucose, in part, via down-regulation of phosphoenol pyruvate carboxykinase (PEPCK). Combining fenofibrate with T0901317 caused greater reduction in serum glucose, suggesting an additive effect. The mechanism of lipid and glucose lowering in KKAy mice was examined. Liver PEPCK showed down-regulation in all treatment groups with fenofibrate showing greater effects. Combination of fenofibrate with T090317 showed additive effects on PEPCK down-regulation. Fenofibrate decreased hepatic diacyl glycerol acyl transferase 2 (DGAT2) mRNA leading to reduction in triglyceride synthesis. Most importantly, fenofibrate down regulated expression of hepatic and adipose 11beta hydroxysteroid dehydrogenase (11beta-HSD1) gene, which contributed in attenuating diabetic state. Thus, amelioration of antidiabetic and hyperlipidemic state by fenofibrate in KKAy mice occurred via down-regulation of DGAT2, PEPCK and 11beta-HSD1. It is also shown that the undesirable lipogenic effects of T090317 could be dampened by fenofibrate.
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PMID:Fenofibrate ameliorates diabetic and dyslipidemic profiles in KKAy mice partly via down-regulation of 11beta-HSD1, PEPCK and DGAT2. Comparison of PPARalpha, PPARgamma, and liver x receptor agonists. 1924 4

Previous studies demonstrated that liver X receptor (LXR) agonists inhibit human immunodeficiency virus (HIV) replication by upregulating cholesterol transporter ATP-binding cassette A1 (ABCA1), suppressing HIV production, and reducing infectivity of produced virions. In this study, we extended these observations by analyzing the effect of the LXR agonist T0901317 [N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide] on the ongoing HIV infection and investigating the possibility of using LXR agonist for pre-exposure prophylaxis of HIV infection in a humanized mouse model. Pre-exposure of monocyte-derived macrophages to T0901317 reduced susceptibility of these cells to HIV infection in vitro. This protective effect lasted for up to 4 days after treatment termination and correlated with upregulated expression of ABCA1, reduced abundance of lipid rafts, and reduced fusion of the cells with HIV. Pre-exposure of peripheral blood leukocytes to T0901317 provided only a short-term protection against HIV infection. Treatment of HIV-exposed humanized mice with LXR agonist starting 2 weeks postinfection substantially reduced viral load. When eight humanized mice were pretreated with LXR agonist prior to HIV infection, five animals were protected from infection, two had viral load at the limit of detection, and one had viral load significantly reduced relative to mock-treated controls. T0901317 pretreatment also reduced HIV-induced dyslipidemia in infected mice. In conclusion, these results reveal a novel link between LXR stimulation and cell resistance to HIV infection and suggest that LXR agonists may be good candidates for development as anti-HIV agents, in particular for pre-exposure prophylaxis of HIV infection.
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PMID:Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection. 2612 33