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Raza et al. Hepatoma Res 2019;5:42 I http://dx.doi.org/10.20517/2394-5079.2019.014 Page 5 of 11

[65]
and abnormal methylation of tumour suppressor genes are found the livers of NAFLD patients . ER
[66]
stress also contributes to hepatocyte injury and carcinogenesis in NASH . Thus, the cross-talk among
oxidative stress, ER stress and cell death pathways likely plays a role in the development of NASH and its
[67]
progression to HCC . Similar to oxidative and ER stress, autophagy dysregulation may be involved in the
[68]
[69]
progression of NASH to HCC . In this regard, impaired autophagy leads to defective lipid metabolism ,
[70]
[72]
[71]
proteotoxicity , mitochondrial dysfunction and inflammation , all of which can contribute to HCC
induction.
Several xenobiotic metabolising genes of the aldo-keto reductase family show parallel induction in NASH
and HCC, suggesting a genetic link between NASH and its progression to HCC [73-76] . Thus, disturbance
in hepatic cell metabolism can lead to increased cell death, DNA damage, immune cell activation and
[57]
compensatory proliferation . These changes in hepatic cells activate HSCs and induce fibrosis. If tumour
surveillance and DNA damage repair are impaired in NASH, pre-malignant cells can develop, and, after
critical genetic/epigenetic changes, they become clones that progress to HCC. Therefore, the cumulative
effects of oxidative stress and proliferative response during inflammation and fibrosis are thought to drive
[57]
the progression of HCC .
Gut microbiota
“Gut microbiota” refers to populations of bacteria hosted by the adult human intestine, which maintain a
symbiotic relationship with the host and have a key role in the host immune system. They perform various
functions in the body such as digestion of inaccessible nutrients, synthesis of vitamins and resistance
[77]
to pathogens . They are known to ferment carbohydrates such as cellulose and xylans into short-chain
fatty acids (SCFAs). The liver is exposed to gut-derived products by portal circulation, which provides
a defence against bacterial toxins. SCFAs improve hepatic autophagy and gut barrier function, and
reduce the permeability of bacterial toxins. These gut products can reduce pro-inflammatory pathways
and insulin resistance, which are associated with the progression of chronic liver disease [78,79] . The gut
[80]
microbiota composition is dynamic and may be influenced by diet, hygiene and the use of antibiotics .
The modification of the normal microbiota termed as “dysbiosis” is believed to be associated with the
progression of NAFLD and other chronic metabolic diseases [81-85] .

[86]
Dysbiosis in gut flora has been associated with HCC incidence in humans and animal models . Mice kept
in germ-free conditions or given antibiotics tend to develop fewer and smaller HCCs [87,88] . At the molecular
level, dysbiosis of the gut microbiota leads to an increase in secretion of inflammatory cytokines, such as
tumour necrosis factor alpha and interleukin-8 (IL-8) along with the activation of toll like receptor (TLR)-
4 and TLR-9, resulting in production of IL-1β by Kupffer cells, which are star-shaped (stellate) phagocytic
cells located in the liver. IL-1β promotes lipid accumulation and apoptosis in hepatocytes, causing steatosis
and inflammation, as well as activation of HSCs to produce fibrogenic mediators, and accelerate HCC
establishment [89-92] . Furthermore, dysbiosis promotes the development of NAFLD-associated HCC by
modifying bile acid metabolism. Specifically, alterations in the composition of the gut microbiota can result
in higher levels of deoxycholic acid and the activation of its receptor farnesoid X receptor, which provokes
a senescence-associated secretory phenotype in HSCs, resulting in the secretion of various inflammatory
and tumour-promoting factors in the liver, thus promoting the development of HCCs [87,93] [Figure 1]. To
summarise, the intestinal microbiota may promote the development of NAFLD-associated cirrhosis and
HCC by increasing inflammatory cytokine secretion, activating TLR-4 and TLR-9 and modifying bile acid
metabolism.

Immunological pathways
Metabolic stress not only leads to increased ROS generation but also triggers the inflammatory responses,
which are a pre-requisite for the progression of NASH-associated HCC. Insulin resistance and oxidative