Additive Effects of Nicotine and High-Fat Diet on Hepatocellular Apoptosis in Mice: Involvement of Caspase 2 and Inducible Nitric Oxide Synthase-Mediated Intrinsic Pathway Signaling

R. Ivey; M. Desai; K. Green; I. Sinha-Hikim; T. C. Friedman; A. P. Sinha-Hikim

doi:10.1055/s-0034-1375610

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2014; 46(08): 568-573
DOI: 10.1055/s-0034-1375610

Endocrine Research

Additive Effects of Nicotine and High-Fat Diet on Hepatocellular Apoptosis in Mice: Involvement of Caspase 2 and Inducible Nitric Oxide Synthase-Mediated Intrinsic Pathway Signaling

R. Ivey

¹Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA

,

M. Desai

¹Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA

,

K. Green

¹Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA

,

I. Sinha-Hikim

¹Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA

²David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, USA

,

T. C. Friedman

¹Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA

²David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, USA

,

A. P. Sinha-Hikim

¹Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA

› Institutsangaben

Abstract

Smoking is a major risk factor for diabetes and cardiovascular disease and may contribute to nonalcoholic fatty liver disease (NAFLD). The health risk associated with smoking is exaggerated by obesity and is the leading causes of morbidity and mortality worldwide. We recently demonstrated that combined treatment with nicotine and a high-fat diet (HFD) triggers greater oxidative stress, activates hepatocellular apoptosis, and exacerbates HFD-induced hepatic steatosis. Given that hepatocellular apoptosis plays a pivotal role in the pathogenesis of NAFLD, using this model of exacerbated hepatic steatosis, we elucidated the signal transduction pathways involved in HFD plus nicotine-induced liver cell death. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice daily IP injections of 0.75 mg/kg BW of nicotine or saline for 10 weeks. High-resolution light microscopy revealed markedly higher lipid accumulation in hepatocytes from mice received HFD plus nicotine, compared to mice on HFD alone. Addition of nicotine to HFD further resulted in an increase in the incidence of hepatocellular apoptosis and was associated with activation of caspase 2, induction of inducible nitric oxide synthase (iNOS), and perturbation of the BAX/BCL-2 ratio. Together, our data indicate the involvement of caspase 2 and iNOS-mediated apoptotic signaling in nicotine plus HFD-induced hepatocellular apoptosis. Targeting the caspase 2-mediated death pathway may have a protective role in development and progression of NAFLD.

Key words

nicotine - high-fat diet - oxidative stress - caspase 2 - iNOS - apoptosis - hepatic steatosis

Volltext

Referenzen

References
1 He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, Wang J, Chen CS, Chen J, Wildman RP, Klag MJ, Whelton PK. Major causes of death among men and women in China. N Engl J Med 2005; 353: 1124-1134
2 Barnes PJ. New concepts in chronic obstructive pulmonary disease. Ann Rev Med 2003; 54: 113-129
3 Zaher C, Halbert R, Dubios R, George D, Nonikov D. Smoking-related diseases: the importance of COPD. Int J Tuberc Lung 2004; 8: 1423-1428
4 Hudson NL, Mannino DM. Tobacco use: a chronic illness?. J Community Health 2010; 35: 549-553
5 Hamabe A, Uto H, Imamura Y, Kusano K, Mawatari S, Kumagai K, Kure T, Tamai T, Moriuchi A, Sakiyama T, Oketani M, Ido A, Tsubouchi H. Impact of cigarette smoking on onset of nonalcoholic fatty liver disease over a 10-year period. J Gastroenterol 2011; 46: 769-778
6 Zein CO, Unalp A, Colvin R, Liu Y-C, McCullough AJ. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease. J Hepatol 2011; 54: 753-759
7 Azzalini L, Ferrer E, Ramalho LN, Moreno M, Dominguez M, Colmenero J, Peinado VI, Barbera JA, Arroyo V, Gines P, Caballeria J, Bataller R. Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats. Hepatology 2010; 5: 1567-1576
8 Yuan H, Shyy JY, Martins-Green M. Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1. J Hepatol 2009; 51: 535-547
9 Haslam DW, James WP. Obesity. Lancet 2005; 366: 1197-1209
10 Chiolero A, Faeh D, Paccaud F, Cornuz J. Consequences of smoking for body weight, body fat distribution, and insulin resistance. Am J Clin Nutr 2008; 87: 801-809
11 Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 2008; 118: 829-838
12 Trauner M, Arrease M, Wangner M. Fatty liver and lipotoxicity. Biochem Biophys Acta 2010; 1801: 299-310
13 Kojima H, Sakurai S, Uemura M, Fukui H, Morimoto H, Tamagawa Y. Mitochondrial abnormality and oxidative stress in nonalcoholic steatohepatitis. Alcohol Clin Exp Res 2007; 31 (Suppl. 01) S61-S66
14 Mantena S, King A, Andringa K, Eccleston H, Bailey S. Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol 2008; 44: 1259-1272
15 Puri P, Mirshahl F, Cheung O, Natarajan R, Maher JW, Kellum JM, Sanyal AJ. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134: 568-576
16 Ferreira DM, Castro RE, Machado MV, Evangelista T, Silvestre A, Costa A, Coutinho J, Carepa F, Cortez-Pinto H, Rodrigues CM. Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease. Diabetologia 2011; 54: 1788-1798
17 Friedman TC, Sinha-Hikim I, Parveen M, Najjar SM, Liu Y, Mangubat M, Shin C-S, Lyzlov A, Ivey R, Shaheen M, French SW, Sinha-Hikim AP. Additive effects of nicotine and high-fat diet on hepatic steatosis in male mice. Endocrinology 2012; 153: 5809-5820
18 Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 2002; 297: 1352-1354
19 Braga M, Sinha Hikim AP, Datta S, Ferrini M, Brown D, Kovacheva EL, Gonzalez-Cadavid NF, Sinha-Hikim I. Involvement of oxidative stress and caspase 2-mediated intrinsic pathway signaling in age-related increase in muscle cell apoptosis in mice. Apoptosis 2008; 13: 822-832
20 Prasad V, Chandele A, Jagtap JC, Kumar S, Shastry P. ROS-triggered caspase 2 activation and feedback amplification loop in b-carotene-induced apoptosis. Free Radic Biol Med 2006; 41: 431-442
21 Tamm C, Zhivotovsky B, Ceccatelli S. Caspase-2 activation in neural stem cells undergoing stress-induced apoptosis. Apoptosis 2008; 13: 354-363
22 Sinha-Hikim I, Braga M, Shen R, Sinha Hikim AP. Involvement of c-Jun NH₂-terminal kinase and nitric oxide-mediated mitochondria-dependent intrinsic pathway signaling in cardiotoxin-induced muscle cell death: role of testosterone. Apoptosis 2007; 12: 1965-1978
23 Biswas N, Mahato SK, Chowdhury AA, Manna A, Vinayagam J, Chatterjee S, Jaisankar P, Chaudhuri U, Bandyopadhyay S. CB3E induces iNOS expression by ROS-dependent JNK and ERK activation for apoptosis of leukemia cells. Apoptosis 2012; 17: 612-626
24 Fujita K, Nozaki Y, Yoneda M, Wada K, Takahashi H, Kirikoshi H, Inamori M, Saito S, Iwasaki T, Terauchi Y, Maeyama S, Nakajima A. Nitric oxide plays a crucial role in the development/progression of nonalcoholic steatohepatitis in the choline-deficient, l-amino acid-defined diet-fed rat model. Alcohol Clin Expt Res 2010; 34 (Suppl. 01) S18-S24
25 Sinha-Hikim I, Sinha-Hikim AP, Shen R, Kim H, French SW, Vaziri ND, Crum A, Rajavashisth TB, Norris KC. A novel cystine based antioxidant attenuates oxidative stress and hepatic steatosis in diet-induced obese mice. Exp Mol Pathol 2011; 91: 419-428
26 Sinha-Hikim I, Friedman TC, Shin C-S, Lee D, Ivey R, Sinha-Hikim AP. Nicotine in combination with a high-fat diet causes intramyocellular mitochondrial abnormalities in male mice. Endocrinology 2014; 155: 865-872
27 Singh R, Wang Y, Schattenberg JM, Xian Y, Czaja MJ. Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation. Am J Physiol Gastrointest Liver Physiol 2009; 297: G907-G917
28 Kathirvel E, Morgan K, Nandgiri G, Sandoval BC, Caudill MA, Bottiglieri T, French SW, Morgan TR. Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine. Am J Physiol Gastrointest Liver Physiol 2010; 299: G1068-G1077
29 He S, Rehman H, Wright GL, Zhong Z. Inhibition of inducible nitric oxide synthase prevents mitochondrial damage and improves survival of steatotic liver grafts. Transplantation 2010; 89: 291-298

Zusatzmaterial

Supporting Information