Activation of Liver X Receptor Induces Macrophage Interleukin-5 Expression

Chen, Yuanli; Duan, Yajun; Kang, Yanhua; Yang, Xiaoxiao; Jiang, Meixiu; Zhang, Ling; Li, Guangliang; Yin, Zhinan; Hu, Wenquan; Dong, Pengzhi; Li, Xiaoju; Hajjar, David P.; Han, Jihong

doi:10.1074/jbc.m112.403394

Cited by 53 publications

(51 citation statements)

References 47 publications

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“…injected with 4% thioglycollate solution (3 ml/mouse) 5 days before the end of the experiment. After euthanasia, peritoneal macrophages were individually collected for determination of CD36 and PPAR␥ expression by Western blot analysis (45).…”

Section: Methodsmentioning

confidence: 99%

“…The cellular lysate was centrifuged with a Microfuge for 15 min at 4°C, and the supernatant was collected as whole cellular extract. Expression of CD36, ERK1/2, pi-ERK1/2, PPAR␥, and pi-PPAR␥ protein in extract was determined by Western blot analysis, respectively (45).…”

Section: Methodsmentioning

confidence: 99%

“…Isolation of Total RNA and Determination of CD36 mRNA Expression by Real Time RT-PCR-After treatment, total RNA was isolated from THP-1/PMA macrophages as described (45). The same amount of total RNA (2 g) from each sample was used to synthesize cDNA with a reverse transcription kit followed by real time PCR using a SYBR Green PCR master mix (Bio-Rad) with the forward primer: 5Ј-TCACTGCGACATGA-TTAATGGTACA-3Ј; and the reverse primer: 5Ј-ACGTCG-GATTCAAATACAGCATAGAT-3Ј.…”

Section: Methodsmentioning

confidence: 99%

“…Extraction of Nuclear Protein and Electrophoretic Mobility Shift Assay (EMSA) of PPAR␥-DNA Binding Activity-After treatment and washing with cold PBS, cells were used to extract nuclear protein followed by determination of the binding activity of PPAR␥ to the PPRE in CD36 promoter by EMSA as described (45). To confirm the specific interaction between the radiolabeled PPRE probe with PPAR␥ protein in nuclear extract, we added either anti-PPAR␥ antibody or excess (ϫ50) unlabeled PPRE probe to the reaction system with nuclear extract of control sample.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Yu¹,

Jiang

Chen

et al. 2016

Journal of Biological Chemistry

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Macrophage CD36 binds and internalizes oxidized low density lipoprotein (oxLDL) to facilitate foam cell formation. CD36 expression is activated by peroxisome proliferator-activated receptor ␥ (PPAR␥). Tamoxifen, an anti-breast cancer medicine, has demonstrated pleiotropic functions including cardioprotection with unfully elucidated mechanisms. In this study, we determined that treatment of ApoE-deficient mice with tamoxifen reduced atherosclerosis, which was associated with decreased CD36 and PPAR␥ expression in lesion areas. At the cellular level, we observed that tamoxifen inhibited CD36 protein expression in human THP-1 monocytes, THP-1/PMA macrophages, and human blood monocyte-derived macrophages. Associated with decreased CD36 protein expression, tamoxifen reduced cellular oxLDL accumulation in a CD36-dependent manner. At the transcriptional level, tamoxifen decreased CD36 mRNA expression, promoter activity, and the binding of the PPAR␥ response element in CD36 promoter to PPAR␥ protein. Tamoxifen blocked ligand-induced PPAR␥ nuclear translocation and CD36 expression, but it increased PPAR␥ phosphorylation, which was due to that tamoxifen-activated ERK1/2. Furthermore, deficiency of PPAR␥ expression in macrophages abolished the inhibitory effect of tamoxifen on CD36 expression or cellular oxLDL accumulation both in vitro and in vivo. Taken together, our study demonstrates that tamoxifen inhibits CD36 expression and cellular oxLDL accumulation by inactivating the PPAR␥ signaling pathway, and the inhibition of macrophage CD36 expression can be attributed to the anti-atherogenic properties of tamoxifen.Tamoxifen (Nolvadex) and its immediate metabolite, 4-hydroxytamoxifen, belong to the class of drugs called selective estrogen receptor modulators (1). Dependent on target tissue/ molecules, tamoxifen can function either as an estrogen receptor (ER) 5 antagonist, such as in the mammary tissue, or as an ER agonist, such as in the endometrium (2). In the breast tissue, inactivation of ER by tamoxifen inhibits the growth of breast cancer cells. Therefore, tamoxifen is the most commonly used anti-hormonal drug for adjuvant treatment of patients with ERpositive breast cancer (2). In addition, tamoxifen has been determined to have a preventive function on breast cancer in the population of women with a high risk of developing this disease (3).Besides the effect on breast cancer, several lines of evidence have demonstrated the cardioprotective effects of tamoxifen. In animal models, tamoxifen reduces atherosclerosis in wild type mice and pro-atherogenic animal models, such as ApoE deficient (ApoE Ϫ/Ϫ ) mice and surgically postmenopausal monkeys (4 -6). In humans, tamoxifen lowers the incidence of fatal myocardial infarction, reduces the intima-media thickness of the common carotid artery in the postmenopausal women, and promotes the endothelium-dependent flow-mediated dilation in male patients with advanced atherosclerosis (7-9).Atherosclerosis is one of the major causes of coronary heart disease and a chronic patholo...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Yu¹,

Jiang

Chen

et al. 2016

Journal of Biological Chemistry

Self Cite

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show abstract

“…After extraction, total cellular proteins were used to determine CD36, PPAR␥ or FABP4 protein expression by Western blotting as described previously (46).…”

Section: Methodsmentioning

confidence: 99%

Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression

Yang¹,

Zhang²,

Chen

et al. 2016

Journal of Biological Chemistry

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Progesterone or its analog, one of components of hormone replacement therapy, may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized LDL (oxLDL) that enhances macrophage/foam cell formation, is activated by the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and the pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression, which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36-dependent manner. Mechanistically, progesterone increased PPAR␥ expression and PPAR␥ promoter activity in a PRdependent manner and the binding of PR with the progesterone response element in the PPAR␥ promoter. Specific deletion of macrophage PPAR␥ (MPPAR␥ KO) expression in mice abolished progesterone-induced macrophage CD36 expression and cellular oxLDL accumulation. We also determined that, associated with gestation and increased serum progesterone levels, CD36 and PPAR␥ expression in mouse adipose tissue, skeletal muscle, and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play dual pathophysiological roles by activating PPAR␥ expression, in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis, and enhances the PPAR␥-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy.Hormone replacement therapy (HRT, 4 estrogen plus progestin) is applied to postmenopausal women to alleviate or/and prevent common complications of female menopause. The initial use of estrogen alone as estrogen replacement therapy for postmenopausal women was reported to cause irregular bleeding and increase the risk of endometrial hyperplasia and carcinoma (1, 2). Later studies demonstrated that addition of a synthetic progesterone (for example, progestogen or progestin, which can demonstrate progestational effects similar to progesterone), can reduce the risk of estrogen-induced bleeding, endometrial hyperplasia, and carcinoma (3). Progesterone is a steroid hormone predominantly produced by the corpus luteum after ovulation and exerts its primary action by activating progesterone receptor (PR) (4).Compared with men at matched ages before menopause, women have much lower rates of cardiovascular disease, which can be attributed to endogenous estrogen production. Indeed, studies with animal models have confirmed the cardioprotective effects of estrogen. For example, treatment of ovariectomized rabbits or monkeys with estrogen reduces high-fat diet-induced atherosclerosis (5-7). However, both clinical observations and animal studies have demonstrated that addition of progestin in HRT attenuated the inhibitory effects of estrogen on atherosclerosis. Compared with placebo,...

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Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice

Smet

Hoecke

Beuckelaer

et al. 2016

Immunity, Inflammation and Disease

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IntroductionLiver X receptors (LXRs) are nuclear receptors that function as cholesterol sensors and regulate cholesterol homeostasis. High cholesterol has been recognized as a risk factor in asthma; however, the mechanism of this linkage is not known.MethodsTo explore the importance of cholesterol homeostasis for asthma, we investigated the contribution of LXR activity in an ovalbumin‐ and a house dust mite‐driven eosinophilic asthma mouse model.ResultsIn both models, airway inflammation, airway hyper‐reactivity, and goblet cell hyperplasia were reduced in mice deficient for both LXRα and LXRβ isoforms (LXRα−/−β−/−) as compared to wild‐type mice. Inversely, treatment with the LXR agonist GW3965 showed increased eosinophilic airway inflammation. LXR activity contributed to airway inflammation through promotion of type 2 cytokine production as LXRα−/−β−/− mice showed strongly reduced protein levels of IL‐5 and IL‐13 in the lungs as well as reduced expression of these cytokines by CD4+ lung cells and lung‐draining lymph node cells. In line herewith, LXR activation resulted in increased type 2 cytokine production by the lung‐draining lymph node cells.ConclusionsIn conclusion, our study demonstrates that the cholesterol regulator LXR acts as a positive regulator of eosinophilic asthma in mice, contributing to airway inflammation through regulation of type 2 cytokine production.

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Activation of Liver X Receptor Induces Macrophage Interleukin-5 Expression

Cited by 53 publications

References 47 publications

Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression

Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice

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