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Non-alcoholic fatty liver disease (NAFLD): a tale of fat and sugar?

Lisa Longato

Author Affiliations

UCL Institute for Liver and Digestive Health, Royal Free Hospital, U3rd Floor, Rowland Hill Street, London NW3 2PF, UK

Fibrogenesis & Tissue Repair 2013, 6:14  doi:10.1186/1755-1536-6-14

The electronic version of this article is the complete one and can be found online at:

Received:4 June 2013
Accepted:14 June 2013
Published:18 July 2013

© 2013 Longato; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The global diffusion of the so-called Western diet, which is enriched in fat and carbohydrates, such as fructose, has been proposed to be an underlying cause of the increased prevalence of metabolic conditions, including non-alcoholic fatty liver disease (NAFLD). This Smart Card summarizes the main metabolic and hepatic histological features of rodent models fed with diets combining high fat and fructose.

Fructose; High-fat diet; High-fructose corn syrup; Mice; NAFLD; Non-alcoholic steatohepatitis; Rats; Western diet


Non-alcoholic fatty liver disease (NAFLD), a condition regarded as the hepatic manifestation of the metabolic syndrome, currently represents the most common cause of chronic liver disease [1]. The condition ranges from simple hepatic fat accumulation (steatosis) to non-alcoholic steatohepatitis, where fat is accompanied by hepatocyte injury, and necroinflammation. This condition poses an increased risk of cirrhosis and hepatocellular carcinoma [1]. The dramatic increase in prevalence of obesity, metabolic syndrome, and NAFLD has been linked to the global diffusion of the Western diet, characterized by excess caloric intake due to increased consumption of processed food and beverages, coupled with a more sedentary lifestyle [2,3]. This has led to a significant increase in sucrose and high-fructose corn syrup consumption, both of which contain similar amounts of glucose and fructose [4]. In the USA, for example, fructose consumption has more than doubled in the last three decades [3]. Excessive fructose consumption has been linked to an increased prevalence of metabolic diseases and growing evidence suggests that it may also contribute to the development and severity of NAFLD by exacerbating fat deposition, inflammation, and, possibly fibrosis [5]. Mechanistically, fructose may contribute to NAFLD by promoting de-novo lipogenesis, insulin resistance, oxidative stress, bacterial overgrowth, and inflammation [3-7]. The mechanisms responsible for transition to non-alcoholic steatohepatitis are still not completely understood, in part because of the scarcity of animal models that can fully replicate both the histological and metabolic features of human non-alcoholic steatohepatitis [8]. As fructose is likely to act as a dietary ‘second hit’ [5], effort has recently been put into developing novel experimental models to recapitulate the Western diet by combining high-fat or high-energy diets and fructose. The aim of this Smart Card is to provide a synthetic and exhaustive source for rapid consultation of the currently proposed rodent models of diets combining high fat and fructose, summarizing the metabolic and hepatic consequences of such combinations (Table 1).

Table 1. Metabolic and hepatic features of rodent models fed with diets combining high fat and fructose


GTT-AUC: Glucose tolerance test: area under the curve; HOMA-IR: Homeostasis model of assessment - insulin resistance; NAFLD: Non-alcoholic fatty liver disease; w/v: Weight by volume.

Competing interests

The author declares that she has no competing interest.


  1. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ: The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.

    Gastroenterology 2012, 142:1592-1609. PubMed Abstract | Publisher Full Text OpenURL

  2. Anania FA: Non-alcoholic fatty liver disease and fructose: bad for us, better for mice.

    J Hepatol 2011, 55:218-220. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  3. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH: The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome.

    Nat Rev Gastroenterol Hepatol 2010, 7:251-264. PubMed Abstract | Publisher Full Text OpenURL

  4. Samuel VT: Fructose induced lipogenesis: from sugar to fat to insulin resistance.

    Trends Endocrinol Metab 2011, 22:60-65. PubMed Abstract | Publisher Full Text OpenURL

  5. Vos MB, Lavine JE: Dietary fructose in nonalcoholic fatty liver disease.

    Hepatology 2013, 57:2525-2531. PubMed Abstract | Publisher Full Text OpenURL

  6. Nomura K, Yamanouchi T: The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease.

    J Nutr Biochem 2012, 23:203-208. PubMed Abstract | Publisher Full Text OpenURL

  7. Yilmaz Y: Review article: fructose in non-alcoholic fatty liver disease.

    Aliment Pharmacol Ther 2012, 35:1135-1144. PubMed Abstract | Publisher Full Text OpenURL

  8. Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, Masuoko H, Gores G: Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition.

    Am J Physiol Gastrointest Liver Physiol 2011, 301:G825-G834. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  9. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA: Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent.

    Am J Physiol Gastrointest Liver Physiol 2008, 295:G987-G995. PubMed Abstract | Publisher Full Text OpenURL

  10. Kohli R, Kirby M, Xanthakos SA, Softic S, Feldstein AE, Saxena V, Tang PH, Miles L, Miles MV, Balistreri WF, Woods SC, Seeley RJ: High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis.

    Hepatology 2010, 52:934-944. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  11. Wada T, Kenmochi H, Miyashita Y, Sasaki M, Ojima M, Sasahara M, Koya D, Tsuneki H, Sasaoka T: Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet.

    Endocrinology 2010, 151:2040-2049. PubMed Abstract | Publisher Full Text OpenURL

  12. Feillet-Coudray C, Sutra T, Fouret G, Ramos J, Wrutniak-Cabello C, Cabello G, Cristol JP, Coudray C: Oxidative stress in rats fed a high-fat high-sucrose diet and preventive effect of polyphenols: Involvement of mitochondrial and NAD(P)H oxidase systems.

    Free Radic Biol Med 2009, 46:624-632. PubMed Abstract | Publisher Full Text OpenURL

  13. Sohet FM, Neyrinck AM, Pachikian BD, de Backer FC, Bindels LB, Niklowitz P, Menke T, Cani PD, Delzenne NM: Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice.

    Biochem Pharmacol 2009, 78:1391-1400. PubMed Abstract | Publisher Full Text OpenURL

  14. Alisi A, Da SL, Bruscalupi G, Piemonte F, Panera N, De VR, Leoni S, Bottazzo GF, Masotti A, Nobili V: Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease.

    Lab Invest 2011, 91:283-293. PubMed Abstract | Publisher Full Text OpenURL

  15. Aragno M, Tomasinelli CE, Vercellinatto I, Catalano MG, Collino M, Fantozzi R, Danni O, Boccuzzi G: SREBP-1c in nonalcoholic fatty liver disease induced by Western-type high-fat diet plus fructose in rats.

    Free Radic Biol Med 2009, 47:1067-1074. PubMed Abstract | Publisher Full Text OpenURL

  16. Axelsen LN, Lademann JB, Petersen JS, Holstein-Rathlou NH, Ploug T, Prats C, Pedersen HD, Kjolbye AL: Cardiac and metabolic changes in long-term high fructose-fat fed rats with severe obesity and extensive intramyocardial lipid accumulation.

    Am J Physiol Regul Integr Comp Physiol 2010, 298:R1560-R1570. PubMed Abstract | Publisher Full Text OpenURL

  17. Roth CL, Elfers CT, Figlewicz DP, Melhorn SJ, Morton GJ, Hoofnagle A, Yeh MM, Nelson JE, Kowdley KV: Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and toll-like receptor activation.

    Hepatology 2012, 55:1103-1111. PubMed Abstract | Publisher Full Text OpenURL

  18. Poudyal H, Campbell F, Brown L: Olive leaf extract attenuates cardiac, hepatic, and metabolic changes in high carbohydrate-, high fat-fed rats.

    J Nutr 2010, 140:946-953. PubMed Abstract | Publisher Full Text OpenURL

  19. Tsuchiya H, Ebata Y, Sakabe T, Hama S, Kogure K, Shiota G: High-fat, high-fructose diet induces hepatic iron overload via a hepcidin-independent mechanism prior to the onset of liver steatosis and insulin resistance in mice.

    Metabolism 2013, 62:62-69. PubMed Abstract | Publisher Full Text OpenURL

  20. Kawasaki T, Igarashi K, Koeda T, Sugimoto K, Nakagawa K, Hayashi S, Yamaji R, Inui H, Fukusato T, Yamanouchi T: Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis.

    J Nutr 2009, 139:2067-2071. PubMed Abstract | Publisher Full Text OpenURL

  21. Poudyal H, Panchal SK, Ward LC, Waanders J, Brown L: Chronic high-carbohydrate, high-fat feeding in rats induces reversible metabolic, cardiovascular, and liver changes.

    Am J Physiol Endocrinol Metab 2012, 302:E1472-E1482. PubMed Abstract | Publisher Full Text OpenURL

  22. Panchal SK, Wong WY, Kauter K, Ward LC, Brown L: Caffeine attenuates metabolic syndrome in diet-induced obese rats.

    Nutrition 2012, 28:1055-1062. PubMed Abstract | Publisher Full Text OpenURL