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Int. J. Mol. Sci. 2014, 15(5), 8591-8638; doi:10.3390/ijms15058591

Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

1
Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia
2
The University of Queensland Centre for Clinical Research, Brisbane 4029, Australia
3
QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia
4
School of Medicine, the University of Queensland, Brisbane 4006, Australia
*
Author to whom correspondence should be addressed.
Received: 2 February 2014 / Revised: 20 March 2014 / Accepted: 17 April 2014 / Published: 14 May 2014
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
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Abstract

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future.
Keywords: non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; pathogenesis; fibrosis; lipotoxicity; inflammation; immune response; treatment non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; pathogenesis; fibrosis; lipotoxicity; inflammation; immune response; treatment
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Peverill, W.; Powell, L.W.; Skoien, R. Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation. Int. J. Mol. Sci. 2014, 15, 8591-8638.

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