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Cigarette smoke exposure: A novel cofactor of NAFLD progression?

Open AccessPublished:June 10, 2009DOI:https://doi.org/10.1016/j.jhep.2009.05.021
      Cigarette smoke exposure, whether passive or active, carries a high disease burden worldwide [
      • Barnoya J.
      • Glantz S.A.
      Cardiovascular effects of secondhand smoke: nearly as large as smoking.
      ]. In a recent comprehensive assessment of the mortality attributable to modifiable risk factors in the US adult population, tobacco use was held responsible for 467,000 deaths (approximately one out of five) in 2005 [
      • Danaei G.
      • Ding E.L.
      • Mozaffarian D.
      • Taylor B.
      • Rehm J.
      • Murray C.J.
      • et al.
      The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors.
      ]. Despite the large body of evidence documenting the pluriorgan morbidity of tobacco, reports investigating the impact of cigarette smoking on pathogenesis of liver injury have long remained scant. Initial evidence arose from two retrospective studies suggesting that cigarette smoking may increase prevalence and/or severity of alcoholic [
      • Klatsky A.L.
      • Armstrong M.A.
      Alcohol, smoking, coffee, and cirrhosis.
      ] and HBV-related cirrhosis [
      • Yu M.W.
      • Hsu F.C.
      • Sheen I.S.
      • Chu C.M.
      • Lin D.Y.
      • Chen C.J.
      • et al.
      Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers.
      ]. Accordingly, two recent studies in patients with primary biliary cirrhosis identified tobacco use as an independent predictor of advanced fibrosis at presentation [
      • Zein C.O.
      • Beatty K.
      • Post A.B.
      • Logan L.
      • Debanne S.
      • McCullough A.J.
      Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: a cross validated retrospective assessment.
      ,
      • Corpechot C.
      • Gaourar F.
      • Chrétien Y.
      • Chazouillères O.
      • Callender M.E.
      Is smokin a risk factor of more severe disease in rimary biliary cirrhosis?.
      ]. In contrast, in patients with chronic hepatitis C, the impact of tobacco use on fibrosis progression remains controversial [
      • Pessione F.
      • Ramond M.J.
      • Njapoum C.
      • Duchatelle V.
      • Degott C.
      • Erlinger S.
      • et al.
      Cigarette smoking and hepatic lesions in patients with chronic hepatitis C.
      ,
      • Hezode C.
      • Lonjon I.
      • Roudot-Thoraval F.
      • Mavier J.P.
      • Pawlotsky J.M.
      • Zafrani E.S.
      • et al.
      Impact of smoking on histological liver lesions in chronic hepatitis C.
      ] and available data would suggest that cigarette smoking may aggravate necroinflammation, thereby contributing to accelerated fibrogenesis [
      • Pessione F.
      • Ramond M.J.
      • Njapoum C.
      • Duchatelle V.
      • Degott C.
      • Erlinger S.
      • et al.
      Cigarette smoking and hepatic lesions in patients with chronic hepatitis C.
      ,
      • Hezode C.
      • Lonjon I.
      • Roudot-Thoraval F.
      • Mavier J.P.
      • Pawlotsky J.M.
      • Zafrani E.S.
      • et al.
      Impact of smoking on histological liver lesions in chronic hepatitis C.
      ,
      • Wang C.S.
      • Wang S.T.
      • Chang T.T.
      • Yao W.J.
      • Chou P.
      Smoking and alanine aminotransferase levels in hepatitis C virus infection: implications for prevention of hepatitis C virus progression.
      ,
      • Mallat A.
      • Hezode C.
      • Lotersztajn S.
      Environmental factors as disease accelerators during chronic hepatitis C.
      ]. Finally, in line with the carcinogenic properties of tobacco in several organs, a number of studies indicate that cigarette smoking is associated with an increased incidence of hepatocellular carcinoma in cirrhotic patients [
      • Jee S.H.
      • Ohrr H.
      • Sull J.W.
      • Samet J.M.
      Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in Korea.
      ,
      • Marrero J.A.
      • Fontana R.J.
      • Fu S.
      • Conjeevaram H.S.
      • Su G.L.
      • Lok A.S.
      Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.
      ,
      • Chen Z.M.
      • Liu B.Q.
      • Boreham J.
      • Wu Y.P.
      • Chen J.S.
      • Peto R.
      Smoking and liver cancer in China: case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths.
      ,
      • Fujita Y.
      • Shibata A.
      • Ogimoto I.
      • Kurozawa Y.
      • Nose T.
      • Yoshimura T.
      • et al.
      The effect of interaction between hepatitis C virus and cigarette smoking on the risk of hepatocellular carcinoma.
      ].
      Non-alcoholic fatty liver disease (NAFLD), the hepatic hallmark of the metabolic syndrome, is a worrisome rising cause of chronic liver injury closely linked to a sedentary lifestyle and habits associated with it. Besides its known impact on liver-related mortality in the subgroup of patients that progress to NASH [
      • Parekh S.
      • Anania F.A.
      Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease.
      ], NAFLD has also been identified as an independent risk factor of atherosclerosis and cardiovascular diseases [
      • Hamaguchi M.
      • Kojima T.
      • Takeda N.
      • Nagata C.
      • Takeda J.
      • Sarui H.
      • et al.
      Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease.
      ,
      • Targher G.
      • Alberiche M.
      • Zenere M.B.
      • Bonadonna R.C.
      • Muggeo M.
      • Bonora E.
      Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus.
      ,
      • Targher G.
      • Bertolini L.
      • Poli F.
      • Rodella S.
      • Scala L.
      • Tessari R.
      • et al.
      Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients.
      ]. In this issue of the Journal, Yuan et al. provide novel evidence demonstrating that tobacco smoke exposure may accelerate the development of experimental NAFLD [
      • Yuan H.
      • Shyy J-Y.J.
      • Martins-Green M.
      Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1.
      ]. The study extends an earlier report from the group showing that in apo B transgenic mice, chronic environmental (second-hand) smoke exposure is associated to features of atherosclerotic plaque initiation [
      • Yuan H.
      • Wong L.S.
      • Bhattacharya M.
      • Ma C.
      • Zafarani M.
      • Yao M.
      • et al.
      The effects of second-hand smoke on biological processes important in atherogenesis.
      ]. Using the same model, the authors now show that exposure to second-hand smoke potentiates steatogenesis elicited by a high-fat diet, as assessed by red oil staining and hepatic triglyceride quantification [
      • Yuan H.
      • Shyy J-Y.J.
      • Martins-Green M.
      Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1.
      ]. Since increased hepatic lipogenesis has been shown to account for approximately 30% of triglyceride accumulation in steatotic livers [
      • Donnelly K.L.
      • Smith C.I.
      • Schwarzenberg S.J.
      • Jessurun J.
      • Boldt M.D.
      • Parks E.J.
      Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      ], the authors subsequently investigate the impact of second-hand smoke on liver lipogenic pathways. Interestingly, cultured hepatocyte cell lines exposed to second-hand smoke display enhanced accumulation of triglycerides and increased expression of Acetyl CoA Carboxylase (ACC) and Fatty acid synthase (FAS), two key enzymes governing hepatic synthesis of fatty acids. These data therefore indicate that the steatogenic properties of tobacco smoke are at least partly explained by a direct effect on hepatocytes.
      In deciphering molecular determinants underlying tobacco-dependent activation of lipogenesis, the authors focus on two key regulators of lipid metabolism, Sterol regulatory element binding protein-1c (SREBP-1c) and AMP-activated protein kinase (AMP kinase). SREBPs are a family of basic-helix-loop-helix-leucine zipper transcription factors synthesized as inactive precursors embedded in the endoplasmic reticulum [
      • Raghow R.
      • Yellaturu C.
      • Deng X.
      • Park E.A.
      • Elam M.B.
      SREBPs: the crossroads of physiological and pathological lipid homeostasis.
      ]. Activation of SREBPs requires proteolytic cleavage, thereby allowing nuclear translocation and transcriptional activation of target lipogenic genes [
      • Postic C.
      • Girard J.
      Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice.
      ]. Whereas SREBP-2 governs synthesis of cholesterol, SREBP-1c promotes biosynthesis of fatty acids by upregulating enzymes such as ACC and FAS. The serine/threonine protein kinase AMP kinase is an energy sensor that acts as a metabolic master switch [
      • Long Y.C.
      • Zierath J.R.
      AMP-activated protein kinase signaling in metabolic regulation.
      ]. The phosphorylated active form of the enzyme simultaneously inhibits energy-consuming biosynthetic pathways such as lipogenesis and activates ATP-producing catabolic pathways such as fatty acid oxidation [
      • Long Y.C.
      • Zierath J.R.
      AMP-activated protein kinase signaling in metabolic regulation.
      ]. It has been shown that AMP kinase inhibits fatty acid synthesis both by phosphorylating target lipogenic enzymes and downregulating expression of transcription factors such as SREBP-1c [
      • Zhou G.
      • Myers R.
      • Li Y.
      • Chen Y.
      • Shen X.
      • Fenyk-Melody J.
      • et al.
      Role of AMP-activated protein kinase in mechanism of metformin action.
      ,
      • Foretz M.
      • Ancellin N.
      • Andreelli F.
      • Saintillan Y.
      • Grondin P.
      • Kahn A.
      • et al.
      Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver.
      ,
      • Viollet B.
      • Foretz M.
      • Guigas B.
      • Horman S.
      • Dentin R.
      • Bertrand L.
      • et al.
      Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders.
      ]. In accordance with these data, Yuan et al. now demonstrate that second-hand smoke exposure inhibits phosphorylation and activation of AMP kinase, thereby resulting in increased SREBP-1 activity and enhancement of fatty acid synthesis [
      • Yuan H.
      • Shyy J-Y.J.
      • Martins-Green M.
      Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1.
      ].
      This study provides compelling experimental evidence supporting a role of tobacco smoke exposure as a cofactor of NAFLD. In line with the present report, second-hand smoke exposure has also recently been shown to enhance alcoholic steatosis in a model of apoE-/- mice fed an alcohol diet for 4 weeks [
      • Bailey S.M.
      • Mantena S.K.
      • Millender-Swain T.
      • Cakir Y.
      • Jhala N.C.
      • Chhieng D.
      • et al.
      Ethanol and tobacco smoke increase hepatic steatosis and hypoxia in the hypercholesterolemic apoE(−/−) mouse: implications for a multihit hypothesis of fatty liver disease.
      ]; however, in animals fed a control diet, tobacco smoke exposure had no effect on liver triglyceride concentration [
      • Bailey S.M.
      • Mantena S.K.
      • Millender-Swain T.
      • Cakir Y.
      • Jhala N.C.
      • Chhieng D.
      • et al.
      Ethanol and tobacco smoke increase hepatic steatosis and hypoxia in the hypercholesterolemic apoE(−/−) mouse: implications for a multihit hypothesis of fatty liver disease.
      ]. Taken together, these data suggest that tobacco exposure may behave as a cofactor of steatogenesis of diverse origins, by enhancing hepatocyte lipogenesis. Nonetheless, the data by Yuan et al. warrant confirmation in classical models of NAFLD, such as genetically obese leptin deficient ob/ob mice or mice fed a high-fat diet; indeed, apoB transgenic mice fed a high-fat diet are primarily used as a model of atherosclerosis. Moreover, the data also raise several questions with respect to the mechanisms underlying steatogenic properties of second-hand smoke. Thus, besides the aforementioned enhancement in hepatic lipogenesis, sources of hepatic lipids in the steatotic liver include increased lipolysis in the insulin-resistant adipose tissue, reduced channeling of fatty acids to the β-oxidation pathway in the liver, and/or reduced fat export in the form of very low-density lipoproteins [
      • Postic C.
      • Girard J.
      Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice.
      ]. Future experiments should therefore investigate the impact of tobacco smoke exposure on these pathways, in particular on fatty acid influx, inasmuch as recent studies indicate that tobacco exposure predisposes to the development of insulin resistance [
      • Reaven G.M.
      Insulin resistance/compensatory hyperinsulinemia, essential hypertension, and cardiovascular disease.
      ,
      • Henkin L.
      • Zaccaro D.
      • Haffner S.
      • Karter A.
      • Rewers M.
      • Sholinsky P.
      • et al.
      Cigarette smoking, environmental tobacco smoke exposure and insulin sensitivity: the Insulin Resistance Atherosclerosis Study.
      ]. Also, it is well established that AMP kinase is a major inhibitor of liver glucose output and mediates the hypoglycaemic effects of adiponectin and of anti-diabetic drugs such as metformin and thiazolinediones [
      • Long Y.C.
      • Zierath J.R.
      AMP-activated protein kinase signaling in metabolic regulation.
      ,
      • Zhou G.
      • Myers R.
      • Li Y.
      • Chen Y.
      • Shen X.
      • Fenyk-Melody J.
      • et al.
      Role of AMP-activated protein kinase in mechanism of metformin action.
      ]. These data therefore suggest that tobacco smoke might enhance insulin resistance by inhibiting hepatic AMP kinase. Interestingly, the authors previously showed that second-hand smoke exposure reduces serum levels of adiponectin in apoB mice [
      • Yuan H.
      • Wong L.S.
      • Bhattacharya M.
      • Ma C.
      • Zafarani M.
      • Yao M.
      • et al.
      The effects of second-hand smoke on biological processes important in atherogenesis.
      ]. Whether this decrease in adiponectin contributes to the tobacco-dependent inhibition of AMP kinase remains to be investigated.
      Finally, the data reported by Yuan et al. raise the question as to the clinical relevance of these experimental findings, an issue that remains open, given the scarcity of data. As already mentioned, it has been shown that tobacco use predisposes to the development of insulin resistance [
      • Targher G.
      • Alberiche M.
      • Zenere M.B.
      • Bonadonna R.C.
      • Muggeo M.
      • Bonora E.
      Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus.
      ,
      • Ronnemaa T.
      • Ronnemaa E.M.
      • Puukka P.
      • Pyorala K.
      • Laakso M.
      Smoking is independently associated with high plasma insulin levels in nondiabetic men.
      ,
      • Carnethon M.R.
      • Fortmann S.P.
      • Palaniappan L.
      • Duncan B.B.
      • Schmidt M.I.
      • Chambless L.E.
      Risk factors for progression to incident hyperinsulinemia: the Atherosclerosis Risk in Communities Study, 1987–1998.
      ]. Moreover, findings from a large survey of US adolescents indicate that passive and active smoke exposure are strong independent predictors of the presence of the metabolic syndrome [
      • Weitzman M.
      • Cook S.
      • Auinger P.
      • Florin T.A.
      • Daniels S.
      • Nguyen M.
      • et al.
      Tobacco smoke exposure is associated with the metabolic syndrome in adolescents.
      ]. These observations indirectly suggest that tobacco use may indeed enhance NAFLD, the hepatic hallmark of the metabolic syndrome. However, very few studies have specifically evaluated the potential impact of tobacco use on metabolic steatosis heretofore and results have been discrepant. Thus, a cross-sectional German health survey in 2500 adults found no relationship between tobacco use and the presence of NAFLD as assessed by ultrasonography [
      • Haenle M.M.
      • Brockmann S.O.
      • Kron M.
      • Bertling U.
      • Mason R.A.
      • Steinbach G.
      • et al.
      Overweight, physical activity, tobacco and alcohol consumption in a cross-sectional random sample of German adults.
      ]. In contrast, in a longitudinal study of 368 males with a suspicion of NAFLD, as defined by unexplained ALAT elevations, onset of smoking during the course of follow-up was an independent predictor of ALAT deterioration [
      • Suzuki A.
      • Lindor K.
      • St. Saver J.
      • Lymp J.
      • Mendes F.
      • Muto A.
      • et al.
      Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease.
      ].
      In summary, accumulating data suggest that passive or active tobacco exposure may belong to environmental stressors contributing to the progression of liver injury. The report by Yuan et al. extends this assumption to NAFLD and provides compelling evidence indicating that tobacco smoke might alter the regulatory effect of AMP kinase on lipid metabolism. Future studies should closely investigate the clinical relevance of these findings. Nevertheless, in the meantime, tobacco cessation might be considered in the management of patients with NAFLD.

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