Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 44, Issue 7, Pages 1259-1272Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2007.12.029
Keywords
liver; alcohol; obesity; steatosis; mitochondria; oxidative stress; nitric oxide; antioxidants; proteomics; AFLD; ASH; NAFLD; NASH; free radicals
Funding
- NIAAA NIH HHS [AA15172, R01 AA015172, R01 AA015172-04] Funding Source: Medline
- NIDDK NIH HHS [DK73775, R21 DK073775, R21 DK073775-02] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R21DK073775] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA015172] Funding Source: NIH RePORTER
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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical first-hit in the pathogenesis of liver disease. It is proposed that steatosis primes the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or second-hits. Genetic risk factors can also influence the susceptibility to and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunction are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: (1) the two-hit or multi-hit hypothesis, (2) the role of mitochondrial bioenergetic defects and oxidant stress, (3) the interplay between NO and mitochondria in fatty liver disease, (4) genetic risk factors and oxidative stress-responsive genes, and (5) the feasibility of antioxidants for treatment. (C) 2007 Elsevier Inc. All rights reserved.
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