A Possible Link between Non-Alcoholic Steatohepatitis and Hepatocellular Cancer

Non-alcoholic steatohepatitis (NASH) has become a major risk factor for hepatocellular cancer (HCC) due to the worldwide increasing prevalence of obesity. However, the pathophysiology of NASH and its progression to HCC is incompletely understood. Thus, the aim of this study was to generate a model specific NASH-derived HCC cell line. A murine NASH-HCC model was conducted and the obtained cancer cells (N-HCC25) were investigated towards chromosomal aberrations, the expression of cell type-specific markers, dependency on nutrients, and functional importance of mTOR. N-HCC25 exhibited several chromosomal aberrations as compared to healthy hepatocytes. Hepatocytic (HNF4), EMT (Twist, Snail), and cancer stem cell markers (CD44, EpCAM, CK19, Sox9) were simultaneously expressed in these cells. Proliferation highly depended on the supply of glucose and FBS, but not glutamine. Treatment with a second generation mTOR inhibitor (KU-0063794) resulted in a strong decrease of cell growth in a dose-dependent manner. In contrast, a first generation mTOR inhibitor (Everolimus) only slightly reduced cell proliferation. Cell cycle analyses revealed that the observed growth reduction was most likely due to G1/G0 cell cycle arrest. These results indicate that N-HCC25 is a highly proliferative HCC cell line from a NASH background, which might serve as a suitable in vitro model for future investigations of NASH-derived HCC.

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What Does the Future Hold for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis?

Current Vascular Pharmacology ◽

10.2174/157016111705190703102816 ◽

2019 ◽

Vol 17 (5) ◽

pp. 425-428

Author(s):

Michael Doumas ◽

Konstantinos Imprialos ◽

Konstantinos Stavropoulos ◽

Vasilios G. Athyros

Keyword(s):

Cardiovascular Disease ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Hepatocellular Cancer ◽

Morbidity And Mortality ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Number Of Patients ◽

Alcoholic Fatty Liver Disease

: Non-Alcoholic Fatty Liver Disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (>5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. Its prevalence is increasing because of obesity, metabolic syndrome or Type 2 Diabetes Mellitus (T2DM). NAFLD can cause liver inflammation and progress to Non-Alcoholic Steatohepatitis (NASH), fibrosis, cirrhosis or Hepatocellular Cancer (HCC). Nevertheless, Cardiovascular Disease (CVD) is the most common cause of morbidity and mortality in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without. : The newer antidiabetic drugs such as Glucagon Like Peptide-1 Receptor Agonists (GLP-1 RA), Sodium-Glucose co- Transporter-2 inhibitors (SGLT2i), and statins plus ezetimibe, are considered safe by the guidelines, and may have a beneficial effect on NAFLD/NASH as well as Cardiovascular Disease (CVD) morbidity and mortality. : Future drugs seem to have a potential for holding down the evolution of NAFLD and reduce liver- and CVD-related morbidity and mortality, but they will take some years to be approved for routine use. : Until then pioglitazone, GLP-1 RA, SGLT2i, and statins plus ezetimibe, especially in combination might be useful for treating the huge number of patients with NAFLD/NASH.

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