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

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.

Key Points

  • Nonalcoholic fatty liver disease (NAFLD) is commonly associated with the metabolic syndrome

  • NAFLD can progress from a benign form (hepatic steatosis) to a more extreme form (nonalcoholic steatoheaptitis)

  • Secular trends in fructose consumption coincide with those of NAFLD and the metabolic syndrome; fructose is implicated in the pathogenesis of both NAFLD and the metabolic syndrome

  • Hepatic fructose metabolism is reminiscent of that of ethanol; NAFLD and alcoholic fatty liver disease are similar diseases

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Figure 1: Pathways of hepatic lipid metabolism.
Figure 2: Hepatic fructose metabolism.
Figure 3: Association between sugar-sweetened beverage consumption and serum alanine aminotransferase in a population of children seeking obesity treatment at the University of California, San Francisco.164
Figure 4: Molecular renditions of glucose and fructose.
Figure 5: Generation of reactive oxygen species by fructose or ethanol.

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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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Lim, J., Mietus-Snyder, M., Valente, A. et al. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 7, 251–264 (2010). https://doi.org/10.1038/nrgastro.2010.41

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