Long Noncoding RNAs Hepatocyte Nuclear Factor 4A Antisense RNA 1 and Hepatocyte Nuclear Factor 1A Antisense RNA 1 Are Involved in Ritonavir-Induced Cytotoxicity in Hepatoma Cells

Wang, Xiaofei; Yu, Yihang; Wang, Pei; Yang, Kun; Wang, Yiting; Liang, Yan; Zhong, Xiao‐bo; Zhang, Lirong

doi:10.1124/dmd.121.000693

Cited by 8 publications

(6 citation statements)

References 43 publications

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“…Silencing the PXR gene upregulated HNF4α and GLUT2 expression, and PXR overexpression downregulated GLUT2 and HNF4α expression [69]. The mechanistic involvement of the PXR-HNF4α pathway was further confirmed when the long noncoding antisense RNA 1 of HNF4α was recently demonstrated to modulate the expression of PXR and CYP3A4 and increase cytotoxic lactate dehydrogenase and reactive oxygen species in Huh7 and HepG2 cells [70].…”

Section: Impairment In Hepatic Transcription Apoptosis and Immune Res...mentioning

confidence: 87%

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Cheng

2023

IJMS

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Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.

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Section: Impairment In Hepatic Transcription Apoptosis and Immune Res...mentioning

confidence: 87%

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Cheng

2023

IJMS

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“…The siRNAs reported in the literature specifically target 204 [1,9,12,13,44]. However, the shRNA used in a study of Ritonavir-induced hepatoma cells targets multiple transcripts of HNF1A-AS1, specifically 204 and 206 [15]. It is important to note that not all publications provided the shRNA targeting sequences, which means the specific transcripts targeted remain unidentified [12,14,45].…”

Section: Discussionmentioning

confidence: 99%

“…HNF1A-AS1 has also been shown to be involved in an HNF1A mediated transcriptional regulatory network to control the basal and drug-induced expression of drug metabolizing cytochrome P450 (CYP) enzymes in liver cells [12,13]. As a CYP regulator, HNF1A-AS1 can alter susceptibility of cytotoxicity in liver cells and is induced by various drugs, such as acetaminophen [14] and ritonavir [15], which are primarily metabolized by certain CYP enzymes. HNF1A-AS1 regulates CYP expression at both transcription and post-transcription levels.…”

Section: Introductionmentioning

confidence: 99%

Identification and Functional Characterization of Alternative Transcripts of LncRNA HNF1A-AS1 and Their Impacts on Cell Growth, Differentiation, Liver Diseases, and in Response to Drug Induction

Jin,

Nguyen,

Wassef

et al. 2024

ncRNA

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The long non-coding RNA (lncRNA) hepatocyte nuclear factor-1 alpha (HNF1A) antisense RNA 1 (HNF1A-AS1) is an important lncRNA for liver growth, development, cell differentiation, and drug metabolism. Like many lncRNAs, HNF1A-AS1 has multiple annotated alternative transcripts in the human genome. Several fundamental biological questions are still not solved: (1) How many transcripts really exist in biological samples, such as liver samples and liver cell lines? (2) What are the expression patterns of different alternative HNF1A-AS1 transcripts at different conditions, including during cell growth and development, after exposure to xenobiotics (such as drugs), and in disease conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD) cirrhosis, and obesity? (3) Does the siRNA used in previous studies knock down one or multiple transcripts? (4) Do different transcripts have the same or different functions for gene regulation? The presented data confirm the existence of several annotated HNF1A-AS1 transcripts in liver samples and cell lines, but also identify some new transcripts, which are not annotated in the Ensembl genome database. Expression patterns of the identified HNF1A-AS1 transcripts are highly correlated with the cell differentiation of matured hepatocyte-like cells from human embryonic stem cells (hESC), growth and differentiation of HepaRG cells, in response to rifampicin induction, and in various liver disease conditions. The expression levels of the HNF1A-AS1 transcripts are also highly correlated to the expression of cytochrome P450 enzymes, such as CYP3A4, during HepaRG growth, differentiation, and in response to rifampicin induction.

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“…Of these six top regulators, HNF4A-AS1 and NR1I2 were reported to be associated with CYP3A expression [ 29 , 31 ]. Experimental discovery of the role of lncRNA HNF4A-AS1 provides strong validation for the lncRNAs inferred by WGCNA [ 32 , 33 , 34 ]. These results reveal that multiple lncRNAs have robust associations with CYP3A s similar to that of TFs in both liver and small intestine.…”

Section: Discussionmentioning

confidence: 99%

“…According to our results, lncRNAs should also be considered as important factors in CYP3A expression. By including lncRNAs, our study provides new insights into the CYP3A regulation that underlies the interindividual pharmacokinetic and pharmacodynamic variability of CYP3A s. Well-defined regulatory networks may enhance clinical predictions of CYP3A related drug metabolism, with lncRNAs as additional biomarkers of toxicity or metabolism [ 34 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Transcription Factors and ncRNAs Associated with CYP3A Expression in Human Liver and Small Intestine Assessed with Weighted Gene Co-Expression Network Analysis

et al. 2022

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CYP3A4, CYP3A5, and CYP3A7, which are located in a multigene locus (CYP3A), play crucial roles in drug metabolism. To understand the highly variable hepatic expression of CYP3As, regulatory network analyses have focused on transcription factors (TFs). Since long non-coding RNAs (lncRNAs) likely contribute to such networks, we assessed the regulatory effects of both TFs and lncRNAs on CYP3A expression in the human liver and small intestine, main organs of CYP3A expression. Using weighted gene co-expression network analysis (WGCNA) of GTEx v8 RNA expression data and multiple stepwise regression analysis, we constructed TF-lncRNA-CYP3A co-expression networks. Multiple lncRNAs and TFs displayed robust associations with CYP3A expression that differed between liver and small intestines (LINC02499, HNF4A-AS1, AC027682.6, LOC102724153, and RP11-503C24.6), indicating that lncRNAs contribute to variance in CYP3A expression in both organs. Of these, HNF4A-AS1 had been experimentally demonstrated to affect CYP3A expression. Incorporating ncRNAs into CYP3A expression regulatory network revealed additional candidate TFs associated with CYP3A expression. These results serve as a guide for experimental studies on lncRNA-TF regulation of CYP3A expression in the liver and small intestines.

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Long Noncoding RNAs Hepatocyte Nuclear Factor 4A Antisense RNA 1 and Hepatocyte Nuclear Factor 1A Antisense RNA 1 Are Involved in Ritonavir-Induced Cytotoxicity in Hepatoma Cells

Cited by 8 publications

References 43 publications

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Identification and Functional Characterization of Alternative Transcripts of LncRNA HNF1A-AS1 and Their Impacts on Cell Growth, Differentiation, Liver Diseases, and in Response to Drug Induction

Transcription Factors and ncRNAs Associated with CYP3A Expression in Human Liver and Small Intestine Assessed with Weighted Gene Co-Expression Network Analysis

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