title: Apolipoprotein E deficiency and high-fat diet cooperate to trigger lipidosis and inflammation in the lung via the toll-like receptor 4 pathway.
abstract: Apolipoprotein E deficiency (ApoE(-/-)) combined with a high-fat Western-type diet (WD) is known to activate the toll-like receptor (TLR4) pathway and promote atherosclerosis. However, to date, the pathogenic effects of these conditions on the lung have not been extensively studied. Therefore, the present study examined the effects of ApoE(-/-) and a WD on lung injury and investigated the underlying mechanisms. ApoE(-/-) and wild-type mice were fed a WD or normal chow diet for 4, 12 and 24 weeks. Lung inflammation, lung cholesterol content and cytokines profiles in broncho-alveolar lavage fluid (BALF) were determined. TLR4 and its main downstream molecules were analyzed with western blot analysis. In addition, the role of the TLR4 pathway was further validated using TLR4-targeted gene silencing. The results showed that ApoE(-/-) mice developed lung lipidosis following 12 weeks of receiving a WD, as evidenced by an increased lung cholesterol content. Moreover, dependent on the time period of receiving the diet, those mice exhibited pulmonary inflammation, which was manifested by initial leukocyte recruitment (at 4 weeks), by increased alveolar septal thickness and mean linear intercept as well as elevated production of inflammation mediators (at 12 weeks), and by granuloma formation (at 24 weeks). The expression levels of TLR4, myeloid differentiation primary response 88 (MyD88) and nuclear factor kappa B were markedly upregulated in ApoE(-/-) WD mice at week 12. However, these effects were ameliorated by shRNA-mediated knockdown of TLR4. By contrast, ApoE(-/-) ND or wild-type WD mice exhibited low-grade or no inflammation and mild lipidosis. The levels of TLR4 and MyD88 in those mice showed only minor changes. In conclusion, ApoE deficiency acts synergistically with a WD to trigger lung lipidosis and inflammation at least in part via TLR4 signaling.
authors.affiliation: Cardiovascular Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Ouyang
authors.affiliation: Cardiovascular Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Cardiovascular Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.
authors.forename: Huili
authors.initials: H
authors.lastname: Lin
authors.affiliation: Cardiovascular Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Ni
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012, P.R. China.
authors.forename: Huixia
authors.initials: H
authors.lastname: Lu
authors.affiliation: Rheumatism Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cardiovascular Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Rheumatism Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005786:Gene Expression Regulation; D006099:Granuloma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008064:Lipidoses / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002784:Cholesterol