Skip to main content
SpringerLink
Log in

Moderate alcohol consumption diminishes the development of non-alcoholic fatty liver disease (NAFLD) in ob/ob mice

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Using ob/ob mice as a model of non-alcoholic fatty liver disease (NAFLD), we investigated the effect of moderate alcohol intake on the development of NAFLD and molecular mechanisms involved.

Methods

Ob/ob mice were fed water or ethanol solution (2.5 g/kg body weight/day) for 6 weeks, and markers of liver injury, insulin signalling and adiponectin in visceral adipose tissue were determined.

Results

Whereas bodyweight and the degree of liver steatosis did not differ among ob/ob mouse groups, those consuming ethanol had markedly less macrovesicular hepatic fat accumulation, inflammatory alterations and significantly lower transaminase levels. Despite similarly elevated protein levels of tumour necrosis factor α, protein concentrations of plasminogen activator inhibitor 1 were significantly lower in livers of ob/ob mice consuming ethanol in comparison with controls. The hepato-protective property of moderate alcohol ingestion in ob/ob mice was associated with an induction of the sirtuin-1/adiponectin-signalling cascade in visceral fat tissue and an activation of Akt in the liver. Similar effects of moderate alcohol exposure were also found in vitro in 3T3-L1 and AML-12 cells.

Conclusion

These data suggest that moderate alcohol intake may diminish the development of NAFLD through sirtuin-1/-adiponectin-dependent signalling cascades.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ACOX1:

Acyl-coenzyme A oxidase

ADH:

Alcohol dehydrogenase

Akt:

Protein kinase B

AML-12:

Alpha mouse liver 12 cells

AMPK:

Adenosine monophosphate-activated protein kinase

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BAX:

BCL2-associated X protein

b.w.:

Body weight

CCL2:

Chemokine (c–c motif) ligand 2

ELISA:

Enzyme-linked immunosorbent assay

FAS:

Fatty acid synthase

FOXO1:

Forkhead box O1

GK:

Glucokinase

GLUT4:

Glucose transporter type 4

H&E:

Haematoxylin and eosin

IRS-1/2:

Insulin receptor substrate 1/2

NAFLD:

Non-alcoholic fatty liver disease

NAS:

NAFLD activity score

NASH:

Non-alcoholic steatohepatitis

PAI-1:

Plasminogen activator inhibitor 1

PEPCK:

Phosphoenolpyruvate carboxykinase

PPARγ:

Peroxisome proliferator-activated receptor gamma

RT-PCR:

Reverse transcriptase polymerase chain reaction

SIRT1:

Sirtuin-1

SREBP-1c:

Sterol regulatory element-binding protein 1c

TNFα:

Tumour necrosis factor alpha

References

  1. Adams LA, Lymp JF, St SJ, Sanderson SO, Lindor KD, Feldstein A, Angulo P (2005) The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129:113–121

    Article  Google Scholar 

  2. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S (2005) Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 42:44–52

    Article  Google Scholar 

  3. Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK, Sohn CI, Keum DK, Kim BI (2006) Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 21:138–143

    Article  Google Scholar 

  4. Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52:1836–1846

    Article  CAS  Google Scholar 

  5. Lelbach WK (1975) Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse. Ann N Y Acad Sci 252:85–105

    Article  CAS  Google Scholar 

  6. Dunn W, Sanyal AJ, Brunt EM, Unalp-Arida A, Donohue M, McCullough AJ, Schwimmer JB (2012) Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol 57:384–391

    Article  CAS  Google Scholar 

  7. Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, Taniguchi H, Ikeda F, Shiratori Y, Yamamoto K (2011) Alcohol consumption appears to protect against non-alcoholic fatty liver disease. Aliment Pharmacol Ther 33:378–388

    Article  CAS  Google Scholar 

  8. White IR, Altmann DR, Nanchahal K (2002) Alcohol consumption and mortality: modelling risks for men and women at different ages. BMJ 325:191

    Article  Google Scholar 

  9. Gao B, Bataller R (2011) Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141:1572–1585

    Article  CAS  Google Scholar 

  10. Fromenty B, Vadrot N, Massart J, Turlin B, Barri-Ova N, Letteron P, Fautrel A, Robin MA (2009) Chronic ethanol consumption lessens the gain of body weight, liver triglycerides, and diabetes in obese ob/ob mice. J Pharmacol Exp Ther 331:23–34

    Article  CAS  Google Scholar 

  11. Wang Y, Seitz HK, Wang XD (2010) Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats. Alcohol Clin Exp Res 34:567–573

    Article  CAS  Google Scholar 

  12. You M, Considine RV, Leone TC, Kelly DP, Crabb DW (2005) Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 42:568–577

    Article  CAS  Google Scholar 

  13. Shearn CT, Smathers RL, Jiang H, Orlicky DJ, Maclean KN, Petersen DR (2013) Increased dietary fat contributes to dysregulation of the LKB1/AMPK pathway and increased damage in a mouse model of early-stage ethanol-mediated steatosis. J Nutr Biochem 24:1436–1445

    Article  CAS  Google Scholar 

  14. Xu J, Lai KK, Verlinsky A, Lugea A, French SW, Cooper MP, Ji C, Tsukamoto H (2011) Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. J Hepatol 55:673–682

    Article  CAS  Google Scholar 

  15. Assuncao M, Santos-Marques MJ, Monteiro R, Azevedo I, Andrade JP, Carvalho F, Martins MJ (2009) Red wine protects against ethanol-induced oxidative stress in rat liver. J Agric Food Chem 57:6066–6073

    Article  CAS  Google Scholar 

  16. Chiva-Blanch G, Urpi-Sarda M, Ros E, Valderas-Martinez P, Casas R, Arranz S, Guillen M, Lamuela-Raventos RM, Llorach R, Andres-Lacueva C, Estruch R (2013) Effects of red wine polyphenols and alcohol on glucose metabolism and the lipid profile: a randomized clinical trial. Clin Nutr 32:200–206

    Article  CAS  Google Scholar 

  17. Gronbaek M, Jensen MK, Johansen D, Sorensen TI, Becker U (2004) Intake of beer, wine and spirits and risk of heavy drinking and alcoholic cirrhosis. Biol Res 37:195–200

    Article  Google Scholar 

  18. Konrat C, Mennen LI, Caces E, Lepinay P, Rakotozafy F, Forhan A, Balkau B (2002) Alcohol intake and fasting insulin in French men and women. The D.E.S.I.R study. Diabetes Metab 28:116–123

    CAS  Google Scholar 

  19. Rodriguez FD, Simonsson P, Alling C (1992) A method for maintaining constant ethanol concentrations in cell culture media. Alcohol Alcohol 27:309–313

    CAS  Google Scholar 

  20. Kanuri G, Weber S, Volynets V, Spruss A, Bischoff SC, Bergheim I (2009) Cinnamon extract protects against acute alcohol-induced liver steatosis in mice. J Nutr 139:482–487

    Article  CAS  Google Scholar 

  21. Kleiner DE, Brunt EM, Van NM, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321

    Article  Google Scholar 

  22. Spruss A, Henkel J, Kanuri G, Blank D, Puschel GP, Bischoff SC, Bergheim I (2012) Female mice are more susceptible to non-alcoholic fatty liver disease: sex-specific regulation of the hepatic AMP-activated protein kinase—plasminogen activator inhibitor 1-cascade but not the hepatic endotoxin response. Mol Med 18:1346–1355

    Article  CAS  Google Scholar 

  23. Orlicky DJ, Roede JR, Bales E, Greenwood C, Greenberg A, Petersen D, McManaman JL (2011) Chronic ethanol consumption in mice alters hepatocyte lipid droplet properties. Alcohol Clin Exp Res 35:1020–1033

    Article  CAS  Google Scholar 

  24. Qiao L, Shao J (2006) SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J Biol Chem 281:39915–39924

    Article  CAS  Google Scholar 

  25. Blomstrand R, Theorell H (1970) Inhibitory effect on ethanol oxidation in man after administration of 4-methylpyrazole. Life Sci II 9:631–640

    Article  CAS  Google Scholar 

  26. Wu JC, Merlino G, Fausto N (1994) Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha. Proc Natl Acad Sci USA 91:674–678

    Article  CAS  Google Scholar 

  27. Cleophas TJ (1999) Wine, beer and spirits and the risk of myocardial infarction: a systematic review. Biomed Pharmacother 53:417–423

    Article  CAS  Google Scholar 

  28. Nova E, Baccan GC, Veses A, Zapatera B, Marcos A (2012) Potential health benefits of moderate alcohol consumption: current perspectives in research. Proc Nutr Soc 71:307–315

    Article  CAS  Google Scholar 

  29. Rehm J, Baliunas D, Borges GL, Graham K, Irving H, Kehoe T, Parry CD, Patra J, Popova S, Poznyak V, Roerecke M, Room R, Samokhvalov AV, Taylor B (2010) The relation between different dimensions of alcohol consumption and burden of disease: an overview. Addiction 105:817–843

    Article  Google Scholar 

  30. Hidestrand M, Shankar K, Ronis MJ, Badger TM (2005) Effects of light and dark beer on hepatic cytochrome P-450 expression in male rats receiving alcoholic beverages as part of total enteral nutrition. Alcohol Clin Exp Res 29:888–895

    Article  CAS  Google Scholar 

  31. Brien SE, Ronksley PE, Turner BJ, Mukamal KJ, Ghali WA (2011) Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies. BMJ 342:d636

    Article  Google Scholar 

  32. Baffy G (2009) Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol 51:212–223

    Article  CAS  Google Scholar 

  33. Samuel VT, Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148:852–871

    Article  CAS  Google Scholar 

  34. Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights. Science 332:1519–1523

    Article  CAS  Google Scholar 

  35. Purohit V, Gao B, Song BJ (2009) Molecular mechanisms of alcoholic fatty liver. Alcohol Clin Exp Res 33:191–205

    Article  CAS  Google Scholar 

  36. Araki E, Lipes MA, Patti ME, Bruning JC, Haag B III, Johnson RS, Kahn CR (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372:186–190

    Article  CAS  Google Scholar 

  37. Gonzalez-Rodriguez A, Mas Gutierrez JA, Sanz-Gonzalez S, Ros M, Burks DJ, Valverde AM (2010) Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice. Diabetes 59:588–599

    Article  CAS  Google Scholar 

  38. Kubota N, Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R, Tsubamoto Y, Komeda K, Nakano R, Miki H, Satoh S, Sekihara H, Sciacchitano S, Lesniak M, Aizawa S, Nagai R, Kimura S, Akanuma Y, Taylor SI, Kadowaki T (2000) Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes 49:1880–1889

    Article  CAS  Google Scholar 

  39. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904

    Article  CAS  Google Scholar 

  40. Bonnet F, Disse E, Laville M, Mari A, Hojlund K, Anderwald CH, Piatti P, Balkau B (2012) Moderate alcohol consumption is associated with improved insulin sensitivity, reduced basal insulin secretion rate and lower fasting glucagon concentration in healthy women. Diabetologia 55:3228–3237

    Article  CAS  Google Scholar 

  41. Cintra DE, Pauli JR, Araujo EP, Moraes JC, de Souza CT, Milanski M, Morari J, Gambero A, Saad MJ, Velloso LA (2008) Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J Hepatol 48:628–637

    Article  CAS  Google Scholar 

  42. Qin B, Anderson RA, Adeli K (2008) Tumor necrosis factor-alpha directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling. Am J Physiol Gastrointest Liver Physiol 294:G1120–G1129

    Article  CAS  Google Scholar 

  43. Cheng Z, White MF (2011) Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models. Antioxid Redox Signal 14:649–661

    Article  CAS  Google Scholar 

  44. Satoh T (2014) Rho GTPases in insulin-stimulated glucose uptake. Small GTPases 5:e28102

    Article  Google Scholar 

  45. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112:91–100

    Article  CAS  Google Scholar 

  46. Ji L, Zhang X, Liu W, Huang Q, Yang W, Fu F, Ma H, Su H, Wang H, Wang J, Zhang H, Gao F (2013) AMPK-regulated and Akt-dependent enhancement of glucose uptake is essential in ischemic preconditioning-alleviated reperfusion injury. PLoS ONE 8:e69910

    Article  CAS  Google Scholar 

  47. Penumathsa SV, Thirunavukkarasu M, Samuel SM, Zhan L, Maulik G, Bagchi M, Bagchi D, Maulik N (2009) Niacin bound chromium treatment induces myocardial Glut-4 translocation and caveolar interaction via Akt, AMPK and eNOS phosphorylation in streptozotocin induced diabetic rats after ischemia-reperfusion injury. Biochim Biophys Acta 1792:39–48

    Article  CAS  Google Scholar 

  48. Adachi M, Brenner DA (2008) High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase. Hepatology 47:677–685

    Article  CAS  Google Scholar 

  49. Yano W, Kubota N, Itoh S, Kubota T, Awazawa M, Moroi M, Sugi K, Takamoto I, Ogata H, Tokuyama K, Noda T, Terauchi Y, Ueki K, Kadowaki T (2008) Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice. Endocr J 55:515–522

    Article  CAS  Google Scholar 

  50. Nascimento AF, Ip BC, Luvizotto RA, Seitz HK, Wang XD (2013) Aggravation of nonalcoholic steatohepatitis by moderate alcohol consumption is associated with decreased SIRT1 activity in rats. Hepatobiliary Surg Nutr 2:252–259

    Google Scholar 

  51. Liang X, Hu M, Rogers CQ, Shen Z, You M (2011) Role of SIRT1-FoxO1 signaling in dietary saturated fat-dependent upregulation of liver adiponectin receptor 2 in ethanol-administered mice. Antioxid Redox Signal 15:425–435

    Article  CAS  Google Scholar 

  52. Mandal P, Roychowdhury S, Park PH, Pratt BT, Roger T, Nagy LE (2010) Adiponectin and heme oxygenase-1 suppress TLR4/MyD88-independent signaling in rat Kupffer cells and in mice after chronic ethanol exposure. J Immunol 185:4928–4937

    Article  CAS  Google Scholar 

  53. DeCarli LM, Lieber CS (1967) Fatty liver in the rat after prolonged intake of ethanol with a nutritionally adequate new liquid diet. J Nutr 91:331–336

    CAS  Google Scholar 

  54. Campfield LA, Smith FJ, Burn P (1996) The OB protein (leptin) pathway–a link between adipose tissue mass and central neural networks. Horm Metab Res 28:619–632

    Article  CAS  Google Scholar 

  55. Hu E, Liang P, Spiegelman BM (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697–10703

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was in part supported by a Grant from ‘Zentrum für Ernährungsmedizin (ZEM)’ and ‘BMBF (FKZ: 01EA1305)’ (IB).

Conflict of interest

All authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Dornburger Str. 25, 07743, Jena, Germany

    Giridhar Kanuri, Marianne Landmann, Josephine Priebs, Doreen Ziegenhardt, Christian Degen & Ina Bergheim

  2. Department of Nutritional Medicine (180 a), University of Hohenheim, Stuttgart, Germany

    Astrid Spruss, Marina Löscher & Carolin Röhl

Authors
  1. Giridhar Kanuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marianne Landmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Josephine Priebs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Astrid Spruss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marina Löscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Doreen Ziegenhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carolin Röhl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christian Degen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ina Bergheim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ina Bergheim.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanuri, G., Landmann, M., Priebs, J. et al. Moderate alcohol consumption diminishes the development of non-alcoholic fatty liver disease (NAFLD) in ob/ob mice. Eur J Nutr 55, 1153–1164 (2016). https://doi.org/10.1007/s00394-015-0929-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-015-0929-7

Keywords

Search

Navigation