Vanni Holly, Kazeros Angeliki, Wang Rui, Harvey Ben-Gary, Ferris Barbara, De Bishnu P, Carolan Brendan J, Hübner Ralf-Harto, O'Connor Timothy P, Crystal Ronald G
Department of Medicine, Weill Medical College of Cornell University, New York, NY.
Division of Pulmonary and Critical Care Medicine, and Genetic Medicine, Weill Medical College of Cornell University, New York, NY.
Chest. 2009 May;135(5):1197-1208. doi: 10.1378/chest.08-1024. Epub 2009 Feb 2.
Smokers weigh less and have less body fat than nonsmokers. Increased body fat and weight gain are observed following smoking cessation. To assess a possible molecular mechanism underlying the inverse association between smoking and body weight, we hypothesized that smoking may induce the expression of a fat-depleting gene in the airway epithelium, the cell population that takes the brunt of the stress of cigarette smoke.
To assess whether smoking up-regulates expression in the airway epithelium of genes associated with weight loss, microarray analysis was used to evaluate genes associated with fat depletion in large airway epithelial samples obtained by fiberoptic bronchoscopy from healthy smokers and healthy nonsmokers. As a candidate gene we further evaluated the expression of alpha(2)-zinc-glycoprotein 1 (AZGP1), a soluble protein that stimulates lipolysis, induces a reduction in body fat in mice, is associated with the cachexia related to cancer, and is known to be expressed in secretory cells of lung epithelium. AZGP1 protein expression was assessed by Western analysis and localization in the large airway epithelium by immunohistochemistry.
Both microarray and TaqMan analysis demonstrated that AZGP1 messenger RNA levels were higher in the large airway epithelium of healthy smokers compared to healthy nonsmokers (p < 0.05, all comparisons). Western analysis of airway biopsy specimens from smokers compared with those from nonsmokers demonstrated up-regulation of AZGP1 at the protein level, and immunohistochemical analysis demonstrated up-regulation of AZGP1 in secretory as well as neuroendocrine cells of smokers.
In the context that AZGP1 is involved in lipolysis and fat loss, its overexpression in the airway epithelium of chronic smokers may represent one mechanism for the weight difference in smokers vs nonsmokers.
吸烟者体重比不吸烟者轻，体脂也比不吸烟者少。戒烟后会出现体脂增加和体重上升的情况。为了评估吸烟与体重之间负相关关系背后可能的分子机制，我们推测吸烟可能会诱导气道上皮细胞中一种消耗脂肪的基因表达，而气道上皮细胞是首当其冲承受香烟烟雾压力的细胞群体。
为了评估吸烟是否会上调气道上皮细胞中与体重减轻相关基因的表达，我们使用微阵列分析来评估通过纤维支气管镜从健康吸烟者和健康不吸烟者获取的大气道上皮样本中与脂肪消耗相关的基因。作为一个候选基因，我们进一步评估了α(2)-锌糖蛋白1（AZGP1）的表达，它是一种可溶性蛋白，可刺激脂肪分解，能使小鼠体脂减少，与癌症相关的恶病质有关，且已知在肺上皮的分泌细胞中表达。通过蛋白质印迹分析评估AZGP1蛋白表达，并通过免疫组织化学确定其在大气道上皮中的定位。
微阵列分析和TaqMan分析均表明，与健康不吸烟者相比，健康吸烟者大气道上皮中的AZGP1信使核糖核酸水平更高（所有比较的p < 0.05）。对吸烟者与不吸烟者的气道活检标本进行蛋白质印迹分析表明，AZGP1在蛋白质水平上上调，免疫组织化学分析表明吸烟者的分泌细胞和神经内分泌细胞中AZGP1上调。
鉴于AZGP1参与脂肪分解和脂肪减少，其在慢性吸烟者气道上皮中的过度表达可能是吸烟者与不吸烟者体重差异的一种机制。
