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Cytokines and fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is now the
most frequent chronic liver disease that occurs across
all age groups and is recognized to occur in 14-30%
of the general population, representing a serious
and growing clinical problem due to the growing
[32]
prevalence of obesity and overweight. The first
manifestation of hepatic injury is the accumulation
of fat within hepatocytes (steatosis), this is
followed by the development of necroinflammatory
(steatohepatitis) activity that leads to cirrhosis. [33]

The importance of cytokines as molecular
effectors in liver damage has been particularly
well demonstrated in patients and animals ranging
from steatosis to cirrhosis. TNF-α is involved in the
progression from steatohepatitis to cirrhosis, since
it promotes activation of stellate cells, matrix-gene
expression, and matrix remodeling. Recent studies
[34]
have indicated that deficiency of IL-1α in KC reduces
liver inflammation and expression of inflammatory
cytokines, which may implicate KC-derived IL-1α in
steatohepatitis development. [35]

Figure 5: The natural history of alcoholic liver disease. Chronic ethanol Obesity, especially visceral adiposity, is a major risk
consumption leads to fatty liver for more than 90%. But only up to 40% of this [36]
population develops more severe forms of alcoholic liver disease, including factor for NASH in humans. Adipose tissue is a
fibrosis and alcoholic hepatitis. Continuous ethanol consumption finally leads source of free fatty acids (FFA) that are delivered
to liver cirrhosis or HCC and leads to death. HCC: hepatocellular carcinoma
to the liver and a depot for triglycerides that are
thymus derived monocytes helper 17 (Th17) synthesized by hepatocytes and released into the
differentiation and IL-17 production, therefore blood. As producers of TNF-α and IL-6, adipocytes are
[37]
contributing to ethanol induced liver inflammation. considered a component of the immune system.
IL-6 is also released along with IL-10, TNF-α and other Visceral fat, which appears to be less “mature” than
cytokines by KC after alcohol consumption. IL-6 and subcutaneous fat, produces more TNF-α and free
IL-10 are two cytokines that play roles in reducing fatty acids but less adiponectin than subscutaneous
[27]
alcoholic liver injury and inflammation. Elevated fat. Adiponectin antagonizes both the production and
IL-6 is found in patients with ALD. On the other activity of TNF-α; thus the effect of this cytokine is
[28]
hand, IL-6 knockout mice fed chronic alcohol showed potentiated when adiponectin is scarce. In addition,
increased liver fat accumulation, lipid peroxidation, TNF-α inhibits adiponectin. Adiponectin also inhibits
mitochondrial DNA damage, and sensitization of synthesis and uptake of FFA by hepatocytes, while
hepatocytes to TNF-α induced apoptosis, which was stimulating FA oxidation enhancing their sensitivity
to insulin. The combination of low adiponectin and
prevented by the administration of recombinant IL-6. [29] high TNF-α levels in the context of increased hepatic
These findings suggest that IL-6 has a protective effect exposure to FFA results in hepatic steatosis and
at the early phase of ALD. Furthermore, IL-17 can act severe hepatic insulin resistance. [38]
with other cytokines to activate NF-kB which plays a
central role in regulating genetic transcription and Leptin, as one of adipocyte secretions, together with
encoding of inflammatory cytokines, and induce IL- its receptor share structural and functional similarities
8. Recently it was shown that patients with ALD had with the IL-6 family of cytokines, and leptin appears
higher IL-17 plasma levels compared with healthy to play a critical role in the inflammatory response by
subjects. [30] IL-1α is also a potent proinflammatory stimulating leukocyte proliferation and the resulting
cytokine. In both animal model and patient with ALD, increased plasma levels of the proinflammatory
the levels of pro-IL-1β are significantly increased in cytokines such as IL-6 and TNF-α. [39] These cytokines
the liver and serum. [31] influence nitric oxide [40] that induces free radicals

Hepatoma Research | Volume 2 | June 1, 2016 135