Characterization of a cholestasis-specific long non-coding RNAs (lncRNAs) signature in chronic liver disease

‘Cholestasis’ is impaired liver bile excretion that occurs commonly in various chronic liver diseases (CLDs). Chronic cholestasis progresses to fibrosis, cirrhosis, or even fatality. Hence the early detection of cholestasis is crucial. Conventional biomarkers based on liver enzymes and serum metabolites are not sensitive enough to reliably indicate cholestasis. Long-non-coding RNAs (lncRNAs) instead have the potential in disease diagnosis especially due to their involvement in pathophysiological and physiological processes and high expression found in different cancer types. We hypothesize that lncRNAs can indicate hepatocyte changes due to cholestasis.

To elucidate this, HepG2 cells were treated with chenodeoxycholic acid (CDCA) and the Farnesoid-X receptor (FXR) agonist GW4064. Within 12 hours at subtoxic levels, cholestasis-related genes were induced, and RNA changes were analyzed via next-generation sequencing and bioinformatics statistical analysis. Four lncRNAs (HNF4-AS1, LINC02732, LINC01488, and Lnc-CCL18-68) showed significant regulation of the 14 commonly regulated lncRNAs in CDCA and GW4064 treated HepG2’s. Protein coding gene pathway enrichment analysis on the REACTOME database revealed an association between lncRNAs and biological processes related to bile acid and cholesterol synthesis. Comparison with publicly available microarray dataset of cholestatic patients and other invitro models, confirmed the specificity of this signature to cholestasis.

Our study demonstrates that in vitro models can identify a unique lncRNA signature specific to liver cholestasis. Changes in lncRNA expression can be detected already under subtoxic conditions, making them potential biomarkers for early-stage CLD patients as well as other liver disease stages such as steatosis, cirrhosis to identify specific targeted therapies.

Publication History

Article published online:
23 January 2024