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Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites

Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of... “…the cause of steatosis, and not the fat accumulation by itself, produces cirrhosis”—Heribert Thaler, 1975 1 W ith nonalcoholic steatohepatitis (NASH), NASH cirrhosis, and NASH‐related hepatocellular carcinoma becoming increasingly prevalent, the need for effective therapies has never been greater. Unfortunately, our understanding of what causes NASH at the molecular level remains mostly speculative, and thus our ability to design clinical trials that test rationally designed therapies is limited. More than a decade has passed since Christopher Day and Oliver James first proposed the oft‐cited two‐hit hypothesis of nonalcoholic fatty liver disease (NAFLD) to explain the pathogenesis of NASH. 2 , 3 According to this appealing hypothesis, the accumulation of lipid in the form of triglyceride is needed for the development of NASH and thus constitutes the first “hit” in this disease. The cause of injury in the setting of lipid‐loaded hepatocytes was proposed to be oxidant stress leading to lipid peroxidation in the milieu of ample substrate. This second “hit” then triggers the necroinflammatory changes that we recognize histopathologically as NASH. Although this hypothesis has intuitive appeal, emerging data now suggests that in the liver, as in other organs, triglyceride accumulation in the form of lipid droplets truly http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Hepatology Wiley

Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites

Hepatology , Volume 52 (2) – Aug 1, 2010

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References (204)

Publisher
Wiley
Copyright
Copyright © 2010 American Association for the Study of Liver Diseases
ISSN
0270-9139
eISSN
1527-3350
DOI
10.1002/hep.23719
pmid
20683968
Publisher site
See Article on Publisher Site

Abstract

“…the cause of steatosis, and not the fat accumulation by itself, produces cirrhosis”—Heribert Thaler, 1975 1 W ith nonalcoholic steatohepatitis (NASH), NASH cirrhosis, and NASH‐related hepatocellular carcinoma becoming increasingly prevalent, the need for effective therapies has never been greater. Unfortunately, our understanding of what causes NASH at the molecular level remains mostly speculative, and thus our ability to design clinical trials that test rationally designed therapies is limited. More than a decade has passed since Christopher Day and Oliver James first proposed the oft‐cited two‐hit hypothesis of nonalcoholic fatty liver disease (NAFLD) to explain the pathogenesis of NASH. 2 , 3 According to this appealing hypothesis, the accumulation of lipid in the form of triglyceride is needed for the development of NASH and thus constitutes the first “hit” in this disease. The cause of injury in the setting of lipid‐loaded hepatocytes was proposed to be oxidant stress leading to lipid peroxidation in the milieu of ample substrate. This second “hit” then triggers the necroinflammatory changes that we recognize histopathologically as NASH. Although this hypothesis has intuitive appeal, emerging data now suggests that in the liver, as in other organs, triglyceride accumulation in the form of lipid droplets truly

Journal

HepatologyWiley

Published: Aug 1, 2010

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