Journal
PROGRESS IN LIPID RESEARCH
Volume 52, Issue 1, Pages 165-174Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.plipres.2012.10.004
Keywords
Lipoapoptosis; Phospholipid composition; Endoplasmic reticulum stress; Oxidative stress; Mitochondrial dysregulation; Triglyceride synthesis
Funding
- National Science Foundation (NSF) [CBET-0955251]
- Vanderbilt Diabetes Research and Training Center [NIH DK020593]
- NSF
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020593, P60DK020593] Funding Source: NIH RePORTER
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The steady rise in Western obesity rates has been closely linked to significant increases in a multitude of accompanying health problems including non-alcoholic fatty liver disease (NAFLD). NAFLD severity ranges from simple steatosis to acute steatohepatitis, but the molecular mechanisms controlling progression of this disease are poorly understood. Recent literature suggests that elevated free fatty acids (FFAs), especially saturated FFAs, may play an important role in lipotoxic mechanisms, both in experimental models and in NAFLD patients. This review highlights important cellular pathways involved in hepatic lipotoxicity and how the degree of intrahepatic lipid saturation controls cell fate in response to an elevated FFA load. Relevant cellular processes that have been causally linked to lipid-induced apoptosis, known as lipoapoptosis, include endoplasmic reticulum (ER) stress, oxidative stress, mitochondria] dysfunction, and Jun N-terminal kinase (INK) signaling. In contrast, increased triglyceride synthesis has been shown to have a protective effect against lipotoxicity, despite being one of the hallmark traits of NAFLD. Developing a more nuanced understanding of the molecular mechanisms underlying NAFLD progression will lead to more targeted and effective therapeutics for this increasingly prevalent disease, which to date has no proven pharmacologic treatment to prevent or reverse its course. (C) 2012 Elsevier Ltd. All rights reserved.
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