Review

The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome

  • Nature Reviews Gastroenterology & Hepatology 7, 251264 (2010)
  • doi:10.1038/nrgastro.2010.41
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide, and is commonly associated with the metabolic syndrome. Secular trends in the prevalence of these diseases may be associated with the increased fructose consumption observed in the Western diet. NAFLD is characterized by two steps of liver injury: intrahepatic lipid accumulation (hepatic steatosis), and inflammatory progression to nonalcoholic steatohepatitis (NASH) (the 'two-hit' theory). In the first 'hit', hepatic metabolism of fructose promotes de novo lipogenesis and intrahepatic lipid, inhibition of mitochondrial β-oxidation of long-chain fatty acids, triglyceride formation and steatosis, hepatic and skeletal muscle insulin resistance, and hyperglycemia. In the second 'hit', owing to the molecular instability of its five-membered furanose ring, fructose promotes protein fructosylation and formation of reactive oxygen species (ROS), which require quenching by hepatic antioxidants. Many patients with NASH also have micronutrient deficiencies and do not have enough antioxidant capacity to prevent synthesis of ROS, resulting in necroinflammation. We postulate that excessive dietary fructose consumption may underlie the development of NAFLD and the metabolic syndrome. Furthermore, we postulate that NAFLD and alcoholic fatty liver disease share the same pathogenesis.

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Acknowledgements

The authors would like to thank Drs S. Noworolski, P. Tsai, P. Rosenthal, N. Bass, R. Merriman, and R. Krauss for constructive input. Dr. Schwarz's laboratory is supported by an NIH–National Institute of Diabetes and Digestive and Kidney Disease grant (R01 DK078133) and an American Diabetes Association Clinical Research Award (1-08-CR-56).

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Affiliations

  1. Department of Pediatrics, Korea Cancer Center Hospital, Gongneung-dong 215, Nowon-gu, Seoul 139-706, Republic of Korea

    • Jung Sub Lim
  2.  Department of Pediatrics, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0434, USA

    • Michele Mietus-Snyder
    • , Annie Valente
    •  & Robert H. Lustig
  3.  College of Osteopathic Medicine, Touro University, 1310 Johnson Lane, Mare Island, Vallejo, CA 94592, USA

    • Jean-Marc Schwarz

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert H. Lustig.