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Partial LXR agonist reduces atherosclerosis in ApoE‐deficient mice without inducing liver steatosis and hypertriglyceridemia
Author(s) -
Kratzer Adelheid,
Buchebner Marlene,
Becker Tatjana M.,
Pfeifer Thomas,
Uray Georg,
Ebner Birgit,
Rathke Nora,
Ahammer Helmut,
Trauner Michael,
Hoefler Gerald,
LevakFrank Sanja,
Levi Moshe,
Kostner Gerhard M.,
Kratky Dagmar
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.803.2
Subject(s) - medicine , hypertriglyceridemia , liver x receptor , endocrinology , steatosis , agonist , apolipoprotein e , lipogenesis , triglyceride , abca1 , sirtuin 1 , cholesterol , chemistry , biology , downregulation and upregulation , receptor , nuclear receptor , lipid metabolism , transporter , biochemistry , gene , transcription factor , disease
Most LXR agonists not only activate genes relevant for the reverse cholesterol transport but also increase lipogenesis. We treated ApoE‐deficient mice with the partial steroidal LXR agonist N,N‐dimethyl‐3β‐hydroxy‐cholenamide (DMHCA). Long‐term administration of DMHCA reduced lesion formation by 20% in male and 22% in female ApoE‐null mice without inducing hypertriglyceridemia or liver steatosis. DMHCA treatment slightly reduced not only plasma total cholesterol, but also plasma triglyceride (TG) concentrations and did not increase hepatic TG levels in male nor female ApoE‐deficient mice. The gene expression levels of ATP binding cassette transporters ABCA1 and G1 and cholesterol 7α‐hydroxylase were increased, while SREBP‐1c mRNA and protein quantity was unchanged. Thus, our data provide evidence that DMHCA is a useful therapeutic agent for the treatment or prevention of atherosclerosis. Currently, we are also evaluating a) potential target genes which are differentially regulated between DMHCA and the non‐steroidal LXR agonist T0901317 and b) short‐ and long‐term treatment of DBA mice with DMHCA. This work was supported by the Austrian Federal Ministry of Education, Science, and Culture, GOLDII, C6.