Abstract
The liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate sterol metabolism and inflammation. We sought to identify previously unknown genes regulated by LXRs in macrophages and to determine their contribution to atherogenesis. Here we characterize a novel LXR target gene, the lipopolysaccharide binding protein (LBP) gene. Surprisingly, the ability of LXRs to control LBP expression is cell-type specific, occurring in macrophages but not liver. Treatment of macrophages with oxysterols or loading with modified LDL induces LBP in an LXR-dependent manner, suggesting a potential role for LBP in the cellular response to cholesterol overload. To investigate this further, we performed bone marrow transplant studies. After 18 weeks of Western diet feeding, atherosclerotic lesion burden was assessed revealing markedly smaller lesions in the LBP(-/-) recipients. Furthermore, loss of bone marrow LBP expression increased apoptosis in atherosclerotic lesions as determined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Supporting in vitro studies with isolated macrophages showed that LBP expression does not affect cholesterol efflux but promotes the survival of macrophages in the setting of cholesterol loading. The LBP gene is a macrophage-specific LXR target that promotes foam cell survival and atherogenesis.
Highlights
The liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate sterol metabolism and inflammation
For real-time PCR analysis of macrophages, each condition represents averages of two independent samples. It has been well-established that LXRs induce the expression of genes involved in reverse cholesterol transport, antiinflammatory signaling, and cell survival in macrophage cell lines
Gene expression analysis demonstrated that lipopolysaccharide binding protein (LBP) expression was induced in a parallel manner to the established LXR target, ABCA1, by GW3965
Summary
All animals (C57Bl/6, greater than 10 generations backcrossed) were housed in a temperature-controlled room under a 12 h light/12 h dark cycle and under pathogen-free conditions. LXR␣Ϫ/Ϫ, LXRϪ/Ϫ, and LXR␣Ϫ/Ϫ mice were originally provided by David Mangelsdorf, University of Texas Southwestern Medical Center, Dallas, TX. LBPϪ/Ϫ mice (C57Bl/6 background) were obtained from Grace Su University of Michigan. Mice were fed either standard chow or Western diet as indicated (21% fat, 0.21% cholesterol; D12079B; Research Diets Inc.). For bone marrow transplantation studies, recipient LDLRϪ/Ϫ mice (11 weeks of age) were lethally irradiated with 900 rads and transplanted with 3 × 106 bone marrow cells from 8-week-old or older donors (WT or LBPϪ/Ϫ) via tail vein injection as previously described [22]. Mice were gavaged with either vehicle or 40 mg/kg of GW3965 once a day for 3 days. Cholesterol and triglyceride levels were measured as previously described [55]. All animal experiments were approved by the Institutional Animal Care and Research Advisory Committee at University of California, Los Angeles
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
