Publication: From fatty liver to fibrosis: A tale of -second hit-
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Date
2013-02-28
Authors
Authors
Basaranoglu, METİN
Basaranoglu, GÖKÇEN
Senturk, HAKAN
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Abstract
Although much is known about how fat accumulates
in the liver, much remains unknown about how this
causes sustained hepatocellular injury. The consequences of injury are recognized as nonalcoholic
steatohepatitis (NASH) and progressive fibrosis. The
accumulation of fat within the hepatocytes sensitizes
the liver to injury from a variety of causes and the regenerative capacity of a fatty liver is impaired. An additional stressor is sometimes referred to as a “second
hit” in a paradigm that identifies the accumulation of
fat as the “first hit”. Possible candidates for the second
hit include increased oxidative stress, lipid peroxidation
and release of toxic products such as malondialdehyde
and 4-hydroxynonenal, decreased antioxidants, adipocytokines, transforming growth factor (TGF)-β, Fas
ligand, mitochondrial dysfunction, fatty acid oxidation
by CYPs (CYP 2E1, 4A10 and 4A14), and peroxisomes,
excess iron, small intestinal bacterial overgrowth, and
the generation of gut-derived toxins such as lipopolysaccharide and ethanol. Oxidative stress is one of the
most popular proposed mechanisms of hepatocellular
injury. Previous studies have specifically observed increased plasma and tissue levels of oxidative stress
markers and lipid peroxidation products, with reduced
hepatic and plasma levels of antioxidants. There is also
some indirect evidence of the benefit of antioxidants
such as vitamin E, S-adenosylmethionine, betaine,
phlebotomy to remove iron, and N-acetylcysteine in
NASH. However, a causal relationship or a pathogenic
link between NASH and oxidative stress has not been
established so far. A number of sources of increased
reactive oxygen species production have been established in NASH that include proinflammatory cytokines
such as tumor necrosis factor (TNF)-α, iron overload,
overburdened and dysfunctional mitochondria, CYPs,
and peroxisomes. Briefly, the pathogenesis of NASH is
multifactorial and excess intracellular fatty acids, oxidant stress, ATP depletion, and mitochondrial dysfunction are important causes of hepatocellular injury in
the steatotic liver.
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Keywords
Fatty liver, Oxidative stress, Fibrosis, Nonalcoholic fatty liver diseases, Nonalcoholic steatohepatitis
Citation
Basaranoglu M., Basaranoglu G., Senturk H., -From fatty liver to fibrosis: A tale of -second hit-, WORLD JOURNAL OF GASTROENTEROLOGY, cilt.19, ss.1158-1165, 2013