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Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease

Nature Clinical Practice Gastroenterology & Hepatology volume 2, pages 46–53 (2005)Cite this article

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome. The metabolic syndrome is characterized by insulin resistance, which is produced by a complex interaction between genetic factors, macronutrient intake and lifestyle that alters the cytokine profile, cell biology and biochemical milieu of the liver, adipose tissue and striated muscle. The resultant disequilibrium in lipid homeostasis causes triglycerides to accumulate in the liver. An increase in oxidative stress, due to the generation of reactive oxygen species as a result of mitochondrial abnormalities and induction of the cytochrome P-450 system could be one mechanism by which the nonalcoholic fatty liver develops into nonalcoholic steatohepatitis. The pathogenesis of cytologic ballooning and Mallory body formation and their role in NAFLD remain to be defined. In addition, inflammation and fibrosis are likely to be secondary to hepatocyte injury and death.

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Figure 1: Triglyceride synthesis from fatty acids.
Figure 2: The contributions of carbohydrate and lipid metabolism to triglyceride formation.
Figure 3: Altered regulation of the intrahepatic pool of free fatty acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
Figure 4: The genesis of mitochondrial dysfunction in nonalcoholic steatohepatitis.

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Acknowledgements

This work was supported in part from a grant from the National Institutes of Health.

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  1. Professor of Medicine and Gastroenterology at Virginia Commonwealth University, Richmond, VA, USA

    Arun J Sanyal

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  1. Arun J Sanyal
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Correspondence to Arun J Sanyal.

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Glossary

INSULIN RESISTANCE

A metabolic state characterized by an impairment in the ability to clear glucose at a given plasma insulin concentration

PEROXISOME

A single membrane organelle that is present in eukaryotic cells and is involved in β oxidation of very long chain fatty acids, bile acid, cholesterol, plasmalogen, amino acid synthesis and purine metabolism

MICROSOME

A small vesicle that is derived from endoplasmic reticulum after homogenization of cells

UBIQUITINYLATED

Covalent attachment of a small highly conserved protein (ubiquitin) to lysine residues of other proteins, thereby marking them for intracellular proteolytic destruction

PROTEOSOMAL

Large protein complex in the cytosol with proteolytic activity that is responsible for degrading proteins that have been marked for destruction by ubiquitylation or by some other means

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Sanyal, A. Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2, 46–53 (2005). https://doi.org/10.1038/ncpgasthep0084

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  • DOI: https://doi.org/10.1038/ncpgasthep0084

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