Molecular Pathogenesis of Nonalcoholic Steatohepatitis- (NASH-) Related Hepatocellular Carcinoma

Abstract

The proportion of obese or diabetic population has been anticipated to increase in the upcoming decades, which rises the prevalence of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Recent evidence indicates that NASH is the main cause of chronic liver diseases and it is an important risk factor for development of hepatocellular carcinoma (HCC). Although the literature addressing NASH-HCC is growing rapidly, limited data is available about the etiology of NASH-related HCC. Experimental studies on the molecular mechanism of HCC development in NASH reveal that the carcinogenesis is relevant to complex changes in signaling pathways that mediate cell proliferation and energy metabolism. Genetic or epigenetic modifications and alterations in metabolic, immunologic, and endocrine pathways have been shown to be closely related to inflammation, liver injury, and fibrosis in NASH along with its subsequent progression to HCC. In this review, we provide an overview on the current knowledge of NASH-related HCC development and emphasize molecular signaling pathways regarding their mechanism of action in NASH-derived HCC.

Targeting Ca2+ Signaling in the Initiation, Promotion and Progression of Hepatocellular Carcinoma

“…As for hepatitis viral infection, a chronic increase in ROS promotes the initiation and progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and then to HCC [ 88 , 89 ]. Increased production of ROS is caused by an accumulation of excess lipid in cytoplasmic lipid droplets in hepatocytes [ 88 , 89 ]. Several Ca 2+ channels, transporters and binding proteins are thought to be important in the initiation and progression of HCC ( Table 5 ).…”

Epidemiology of Liver Cancer in Africa: Current and Future Trends

“…Here, activation of oncogenic mechanisms is via genetic, metabolic, immunologic, and endocrine pathways. 117 The development of hepatic inflammation and fibrosis is affected by deregulated activation of nuclear factor-kappa B (NF-κB). While chronic activation of NF-κB increases the production of tumor necrosis factor (TNF) and HCC development, 118 there is also overexpression of miR-21 in mouse models of NASH which promotes HCC growth and migration of HCC cell lines.…”

Advances and challenges in the management of advanced fibrosis in nonalcoholic steatohepatitis

“… 17 This increased lipid content of hepatocytes may not only cause an increase in the oxidative stress, but also results in increased β-oxidation of free fatty acids in mitochondria, leading to formation for reactive oxygen species, further causing lipid peroxidation, and continuing the cascade as increased secretion of pro-inflammatory cytokines, hepatocyte damage, inflammation, apoptosis and fibrosis. 18 , 19 In fact, this basic ‘hepatic steatosis’ scheme remains a key component of the multiple parallel-hit hypothesis. Excessive calorie intake by unhealthy diet options and sedentary lifestyle are the examples of environmental factors contributing to fatty liver.…”

“…Studies have demonstrated that ingestion of high-fat diet results in impairment of intestinal barrier function. 18 , 23 This can lead to the leakage of bacterial products, most importantly lipopolysaccharides, to the bloodstream. These molecules have been found to play a role in the development of hepatic steatosis and inflammation through toll-like receptors.…”

“…Additionally, chronic endoplasmic reticulum stress produces more reactive oxygen species that triggers hepatocyte inflammation through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and jun-(N)-terminal kinase (JNK) pathways. 18 Another key organelle is the mitochondria, whose functions are disrupted by increased β-oxidation. 30 , 31 Both endoplasmic reticulum stress and mitochondrial dysfunction lead to apoptosis and fibrosis, which are key elements of NASH.…”