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  • Review Article
  • Published:

From NAFLD to NASH to cirrhosis—new insights into disease mechanisms

Abstract

NAFLD has evolved as a serious public health problem in the USA and around the world. In fact, NASH—the most serious form of NAFLD—is predicted to become the leading cause of liver transplantation in the USA by the year 2020. The pathogenesis of NAFLD and NASH, in particular the mechanisms responsible for liver injury and fibrosis, is the result of a complex interplay between host and environmental factors, and is at the centre of intense investigation. In this Review, we focus on recently uncovered aspects of the genetic, biochemical, immunological and molecular events that are responsible for the development and progression of this highly prevalent and potentially serious disease. These studies bring new insight into this complex disorder and have led to the development of novel therapeutic and diagnostic strategies that might enable a personalized approach in the management of this disease.

Key Points

  • The composition of the diet, in particular the types of lipids (mainly omega-6 fatty acids) and carbohydrates (mainly fructose), have an important role in the progression of NAFLD to NASH and fibrosis

  • A complex interplay between the environment (especially diet), host genetics and the gut microflora is crucial for the development and progression of NAFLD

  • Activation of the innate immune system has an essential role in maintaining homeostasis and liver regeneration, as well as disease pathogenesis, acting in a cooperative rather than independent fashion

  • Discoveries that characterized the importance of cell death in NAFLD progression triggered the development of novel therapeutic and diagnostic approaches for NAFLD

  • Various types of cell death contribute to the development of NAFLD; extensive crosstalk and biochemical cooperation exists between these cell death pathways to drive disease progression

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Figure 1: Influence of dietary factors and genetics in development of NAFLD.
Figure 2: Mechanisms of NLRP3 inflammasome activation.
Figure 3: Hepatocellular injury and cell death.

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Acknowledgements

Work by the authors of this Review was funded by NIH (DK076852 and DK082451 to A. E. Feldstein, AI52430 to H. M. Hoffman and T32AI007469 to L. Broderick) and German Research Foundation (DFG-grant 173/2-1 to A. Wree) grants.

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The authors contributed equally to all aspects of this article.

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Correspondence to Ariel E. Feldstein.

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Supplementary information

Supplementary Table 1

Current gene variants identified in human NAFLD and NASH (DOC 55 kb)

Supplementary Box 1

Overview of cell death pathways (DOC 67 kb)

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Wree, A., Broderick, L., Canbay, A. et al. From NAFLD to NASH to cirrhosis—new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 10, 627–636 (2013). https://doi.org/10.1038/nrgastro.2013.149

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