Cigarette Smoking Exacerbates Nonalcoholic Fatty Liver... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Cigarette Smoking Exacerbates Nonalcoholic Fatty Liver Disease in Obese Rats

Azzalini, Lorenzo1,*; Ferrer, Elisabet2,*; Ramalho, Leandra N.3; Moreno, Montserrat1; Domínguez, Marlene1; Colmenero, Jordi1; Peinado, Víctor I.2; Barberà, Joan A.2; Arroyo, Vicente1; Ginès, Pere1; Caballería, Joan1; Bataller, Ramón1,†

1_Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain_

2_Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERes), IDIBAPS and Pneumology Unit, Hospital Clínic, Barcelona, Catalonia, Spain_

3_Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil_

*Address reprint requests to: Liver Unit, Hospital Clínic, Villarroel, 170, 08036 Barcelona, Spain. Email:[email protected]; fax: +34 93 451 5522

Received 23 June 2009; Accepted 2 December 2009

Published online 23 December 2009 in Wiley InterScience (www.interscience.wiley.com).

Supported by grants from the Ministerio de Ciencia y Tecnología, Dirección General de Investigación (SAF 2005-06245), the Instituto de Salud Carlos III (FIS 05/050567, FIS PI 060085, and FIS 04/1424) and the Conselho Nacional de Pesquisa (309327/2006-7). Montserrat Moreno received a grant from the Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). Marlene Domínguez received a grant from the Fundación Banco Bilbao Vizcaya Argentaria (FBBVA).

Potential conflict of interest: Nothing to report.

*These authors contributed equally to this work.

Additional Supporting Information may be found in the online version of this article.

Abstract

The prevalence of cigarette smoking (CS) is increased among obese subjects, who are susceptible to develop nonalcoholic fatty liver disease (NAFLD). We investigated the hepatic effects of CS in control and obese rats. Control and obese Zucker rats were divided into smokers and nonsmokers (n = 12 per group). Smoker rats were exposed to 2 cigarettes/day, 5 days/week for 4 weeks. The effects of CS were assessed by biochemical analysis, hepatic histological examination, immunohistochemistry, and gene expression analysis. Phosphorylation of AKT and extracellular signal-regulated kinase (ERK) and quantification of carbonylated proteins were assessed by western blotting. As expected, obese rats showed hypercholesterolemia, insulin resistance, and histological features of NAFLD. Smoking did not modify the lipidic or glucidic serum profiles. Smoking increased alanine aminotransferase serum levels and the degree of liver injury in obese rats, whereas it only induced minor changes in control rats. Importantly, CS increased the histological severity of NAFLD in obese rats. We also explored the potential mechanisms involved in the deleterious effects of CS. Smoking increased the degree of oxidative stress and hepatocellular apoptosis in obese rats, but not in controls. Similarly, smoking increased the hepatic expression of tissue inhibitor of metalloproteinase-1 and procollagen-alpha2(I) in obese rats, but not in controls. Finally, smoking regulated ERK and AKT phosphorylation. The deleterious effects of CS were not observed after a short exposure (5 days). Conclusion: CS causes oxidative stress and worsens the severity of NAFLD in obese rats. Further studies should assess whether this finding also occurs in patients with obesity and NAFLD. (Hepatology 2010.)