The cross-talk of extracellular signal-regulated protein kinase (ERK) and pregnane X receptor (PXR) and its effect on expression of CYP3A4 and MDR1 genes in primary human hepatocytes and hepatoma cell lines

Tenofovir disoproxil fumarate (TDF) has been regarded as the most potent drug for treating patients with chronic hepatitis B (CHB). However recently, viral mutations associated with tenofovir have been reported. Here, we found a CHB patient with suboptimal response after more than 4 years of TDF treatment. Clonal analysis of hepatitis B virus (HBV) isolated from sequential sera of this patient identified the seven previously reported TDF-resistant mutations (CYELMVI). Interestingly, a threonine to alanine mutation at the 301 amino acid position of the reverse-transcriptase (RT) domain, (rtT301A), was commonly accompanied with CYELMVI at a high rate (72.7%). Since the rtT301A mutation has not been reported yet, we investigated the role of this naturally occurring mutation on the viral replication and susceptibility to tenofovir in various liver cells (hepatoma cells as well as primary human hepatocytes). A cell-based phenotypic assay revealed that the rtT301A mutation dramatically impaired the replication ability with meaningful reduction in sensitivity to tenofovir in hepatoma cell lines. However, attenuated viral replication by the rtT301A mutation was significantly restored in primary human hepatocytes (PHHs). Our findings suggest that the replication capability and drug sensitivity of HBV is different between hepatoma cell lines and PHHs. Therefore, our study emphasizes that validation studies should be performed not only in the liver cancer cell lines but also in the PHHs to understand the exact viral fitness under antiviral pressure in patients.

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Correction: Permissivity of Primary Human Hepatocytes and Different Hepatoma Cell Lines to Cell Culture Adapted Hepatitis C Virus

PLoS ONE ◽

10.1371/journal.pone.0223022 ◽

2019 ◽

Vol 14 (9) ◽

pp. e0223022

Author(s):

Francois Helle ◽

Etienne Brochot ◽

Carole Fournier ◽

Véronique Descamps ◽

Laure Izquierdo ◽

...

Keyword(s):

Cell Culture ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Cell Lines ◽

Hepatoma Cell ◽

Human Hepatocytes ◽

Hepatoma Cell Lines ◽

Primary Human Hepatocytes

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Permissivity of Primary Human Hepatocytes and Different Hepatoma Cell Lines to Cell Culture Adapted Hepatitis C Virus

PLoS ONE ◽

10.1371/journal.pone.0070809 ◽

2013 ◽

Vol 8 (8) ◽

pp. e70809 ◽

Cited By ~ 21

Author(s):

Francois Helle ◽

Etienne Brochot ◽

Carole Fournier ◽

Véronique Descamps ◽

Laure Izquierdo ◽

...

Keyword(s):

Cell Culture ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Cell Lines ◽

Hepatoma Cell ◽

Human Hepatocytes ◽

Hepatoma Cell Lines ◽

Primary Human Hepatocytes

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Transferrin receptor 2 is crucial for iron sensing in human hepatocytes

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00157.2010 ◽

2010 ◽

Vol 299 (3) ◽

pp. G778-G783 ◽

Cited By ~ 17

Author(s):

Chiara Rapisarda ◽

Juliana Puppi ◽

Robin D. Hughes ◽

Anil Dhawan ◽

Sebastien Farnaud ◽

...

Keyword(s):

Cell Lines ◽

Transferrin Receptor ◽

Iron Status ◽

Hepatoma Cell ◽

Human Hepatocytes ◽

Mrna Levels ◽

Hepcidin Expression ◽

Hepatoma Cell Lines ◽

Primary Human Hepatocytes ◽

Transferrin Receptor 2

Hepcidin expression in vivo is regulated in proportion to iron status (i.e., increased by iron loading and decreased in iron deficiency). However, in vitro studies with hepatoma cell lines often show an inverse relationship between iron status and hepcidin expression. Here, we investigated possible molecular mechanisms responsible for the differences in iron sensing between hepatoma cell lines and human primary hepatocytes. RNA was collected from primary human hepatocytes, and HepG2 and HuH7 hepatoma cells were treated with either transferrin-bound and non-transferrin-bound iron. Expression of hepcidin, transferrin receptor 2, HFE, and hemojuvelin were quantified by real-time PCR. Hepcidin expression was increased in primary human hepatocytes following 24-h exposure to holoferric transferrin. In contrast, hepcidin mRNA levels in hepatoma cells were decreased by transferrin. Hepcidin expression was positively correlated with transferrin receptor 2 mRNA levels in primary human hepatocytes. Compared with primary hepatocytes, transferrin receptor 2 expression was significantly lower in hepatoma cell lines; furthermore, there was no correlation between transferrin receptor 2 and hepcidin mRNA levels in either HepG2 or HuH7 cells. Taken together our data suggest that transferrin receptor 2 is a likely candidate to explain the differences in iron sensing between hepatoma cell lines and primary human hepatocytes.

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