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1.
Biochem Pharmacol ; 71(4): 453-63, 2006 Feb 14.
Article in English | MEDLINE | ID: mdl-16325781

ABSTRACT

Liver X receptor (LXR) alpha and LXRbeta are closely related nuclear receptors that respond to elevated levels of intracellular cholesterol by enhancing transcription of genes that control cholesterol efflux and fatty acid biosynthesis. The consequences of inactivation of either LXR isoform have been thoroughly studied, as have the effects of simultaneous activation of both LXRalpha and LXRbeta by synthetic compounds. We here describe the effects of selective activation of LXRalpha or LXRbeta on lipid metabolism. This was accomplished by treating mice genetically deficient in either LXRalpha or LXRbeta with an agonist with equal potency for both isoforms (Compound B) or a synthetic agonist selective for LXRalpha (Compound A). We also determined the effect of these agonists on gene expression and cholesterol efflux in peritoneal macrophages derived from wild-type and knockout mice. Both compounds raised HDL-cholesterol and increased liver triglycerides in wild-type mice; in contrast, in mice deficient in LXRalpha, Compound B increased HDL-cholesterol but did not cause hepatic steatosis. Compound B induced ATP-binding cassette transporter (ABC) A1 expression and stimulated cholesterol efflux in macrophages from both LXRalpha and LXRbeta-deficient mice. Our data lend further experimental support to the hypothesis that LXRbeta-selective agonists may raise HDL-cholesterol and stimulate macrophage cholesterol efflux without causing liver triglyceride accumulation.


Subject(s)
DNA-Binding Proteins/agonists , Lipid Metabolism/physiology , Receptors, Cytoplasmic and Nuclear/agonists , 8-Bromo Cyclic Adenosine Monophosphate/pharmacology , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Administration, Oral , Animals , Cholesterol/metabolism , Cholesterol, HDL/blood , Cholesterol, HDL/metabolism , Cyclic AMP/pharmacology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Isoxazoles/pharmacology , Liver/drug effects , Liver/metabolism , Liver X Receptors , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Structure , Orphan Nuclear Receptors , Phenylurea Compounds/pharmacology , Protein Isoforms/agonists , Protein Isoforms/genetics , Protein Isoforms/physiology , Pyrazines/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/physiology , Reverse Transcriptase Polymerase Chain Reaction , Sterol Regulatory Element Binding Protein 1/genetics , Sterol Regulatory Element Binding Protein 1/metabolism , Triglycerides/blood , Triglycerides/metabolism
2.
J Biol Chem ; 277(50): 48051-7, 2002 Dec 13.
Article in English | MEDLINE | ID: mdl-12377786

ABSTRACT

Several clinical and angiographic intervention trials have shown that fibrate treatment leads to a reduction of the coronary events associated to atherosclerosis. Fibrates are ligands for peroxisome proliferator-activated receptor alpha (PPARalpha) that modulate risk factors related to atherosclerosis by acting at both systemic and vascular levels. Here, we investigated the effect of treatment with the PPARalpha agonist fenofibrate (FF) on the development of atherosclerotic lesions in apolipoprotein (apo) E-deficient mice and human apoA-I transgenic apoE-deficient (hapoA-I Tg x apoE-deficient) mice fed a Western diet. In apoE-deficient mice, plasma lipid levels were increased by FF treatment with no alteration in the cholesterol distribution profile. FF treatment did not reduce atherosclerotic lesion surface area in the aortic sinus of 5-month-old apoE-deficient mice. By contrast, FF treatment decreased total cholesterol and esterified cholesterol contents in descending aortas of these mice, an effect that was more pronounced in older mice exhibiting more advanced lesions. Furthermore, FF treatment reduced MCP-1 mRNA levels in the descending aortas of apoE-deficient mice, whereas ABCA-1 expression levels were maintained despite a significant reduction of aortic cholesterol content. In apoE-deficient mice expressing a human apoA-I transgene, FF increased human apoA-I plasma and hepatic mRNA levels without affecting plasma lipid levels. This increase in human apoA-I expression was accompanied by a significant reduction in the lesion surface area in the aortic sinus. These data indicate that the PPARalpha agonist fenofibrate reduces atherosclerosis in these animal models of atherosclerosis.


Subject(s)
Arteriosclerosis/prevention & control , Fenofibrate/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Animals , Apolipoprotein A-I/genetics , Apolipoprotein A-I/physiology , Apolipoproteins E/genetics , Apolipoproteins E/physiology , Cholesterol/blood , Humans , Liver/metabolism , Mice , Mice, Transgenic , RNA, Messenger/metabolism , Triglycerides/blood
3.
Biochem Biophys Res Commun ; 294(1): 88-94, 2002 May 31.
Article in English | MEDLINE | ID: mdl-12054745

ABSTRACT

Secretory non-pancreatic phospholipase A(2) (sPLA(2)) has been implicated in inflammation and has been found in human atherosclerotic lesions. To test the effect of sPLA(2) deficiency on atherosclerosis, C57BL/Ks mice (apoE(+/+) and PLA(2)(++) were bred with C57BL/6 apoE knockout mice which are sPLA(2)(--) due to a spontaneous mutation. Sibling pairs of mice (apoE(--)/sPLA(2)(++) and apoE(--)/sPLA(2)(--)) on high fat Western diets were dissected at 22 weeks. In vitro enzyme assays confirmed higher serum sPLA(2) activity in the sPLA(2)(++) compared to sPLA(2)(--) for both sexes, while sPLA(2)(--) males had slightly higher serum cholesterol and phospholipids. Analysis of lipoprotein profiles by FPLC showed no effect of sPLA(2) genotype on any measured parameters. Atherosclerosis was quantitated by assaying cholesterol in aortic extracts. Male sPLA(2) trended slightly higher than sPLA(2)(++) with no statistical significance. Female sPLA(2)(++) and sPLA(2)(--) mice showed no significant differences in any of the measured parameters. These results suggest that the endogenous mouse sPLA(2) gene does not significantly affect HDL or atherosclerosis in mice.


Subject(s)
Arteriosclerosis/metabolism , Lipoproteins, HDL/metabolism , Phospholipases A/deficiency , Animals , Apolipoproteins E/genetics , Apolipoproteins E/physiology , Chromatography, High Pressure Liquid , Dietary Fats/administration & dosage , Female , Genotype , Group II Phospholipases A2 , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phospholipases A/metabolism , Sex Factors
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