Cigarette smoking induces overexpression of a fat-depleting gene AZGP1 in the human.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Vanni
Holly
H
Department of Medicine, Weill Medical College of Cornell University, New York, NY.
Kazeros
Angeliki
A
Department of Medicine, Weill Medical College of Cornell University, New York, NY.
Wang
Rui
R
Division of Pulmonary and Critical Care Medicine, and Genetic Medicine, Weill Medical College of Cornell University, New York, NY.
Harvey
Ben-Gary
BG
Department of Medicine, Weill Medical College of Cornell University, New York, NY.
Ferris
Barbara
B
Division of Pulmonary and Critical Care Medicine, and Genetic Medicine, Weill Medical College of Cornell University, New York, NY.
De
Bishnu P
BP
Division of Pulmonary and Critical Care Medicine, and Genetic Medicine, Weill Medical College of Cornell University, New York, NY.
Carolan
Brendan J
BJ
Division of Pulmonary and Critical Care Medicine, and Genetic Medicine, Weill Medical College of Cornell University, New York, NY.
Hübner
Ralf-Harto
RH
Division of Pulmonary and Critical Care Medicine, and Genetic Medicine, Weill Medical College of Cornell University, New York, NY.
O'Connor
Timothy P
TP
Division of Pulmonary and Critical Care Medicine, and Genetic Medicine, Weill Medical College of Cornell University, New York, NY.
Crystal
Ronald G
RG
Division of Pulmonary and Critical Care Medicine, and Genetic Medicine, Weill Medical College of Cornell University, New York, NY. Electronic address: geneticmedicine@med.cornell.edu.
D054392:Adipokines; D000328:Adult; D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism*; D001999:Bronchoscopy; D002352:Carrier Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008066:Lipolysis / Q000235:genetics*; D008297:Male; D040081:Protein Array Analysis; D012907:Smoking / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation; D015431:Weight Loss / Q000235:genetics*; D000090203:Zn-Alpha-2-Glycoprotein
D054392:Adipokines; D002352:Carrier Proteins; D006023:Glycoproteins; C488891:AZGP1 protein, human; D000090203:Zn-Alpha-2-Glycoprotein