Our emerging understanding of the roles of long non-coding RNAs in normal liver function, disease, and malignancy

Abstract

Long non-coding RNAs (lncRNAs) are important biological mediators that regulate numerous cellular processes. New experimental evidence suggests that lncRNAs play essential roles in liver development, normal liver physiology, fibrosis, and malignancy, including hepatocellular carcinoma and cholangiocarcinoma. In this review, we summarise our current understanding of the function of lncRNAs in the liver in both health and disease, as well as discuss approaches that could be used to target these non-coding transcripts for therapeutic purposes.

Keywords: ABCA1, ATP-binding cassette transporter A1; ACTA2/ɑ-SMA, α-smooth muscle actin; APO, apolipoprotein; ASO, antisense oligonucleotides; BDL, bile duct ligation; CCA, cholangiocarcinoma; CCl4, carbon tetrachloride; COL1A1, collagen type I α 1; CYP, cytochrome P450; Cholangiocarcinoma; DANCR, differentiation antagonising non-protein coding RNA; DE, definitive endoderm; DEANR1, definitive endoderm-associated lncRNA1; DIGIT, divergent to goosecoid, induced by TGF-β family signalling; DILC, downregulated in liver cancer stem cells; EST, expression sequence tag; EpCAM, epithelial cell adhesion molecule; FBP1, fructose-bisphosphatase 1; FENDRR, foetal-lethal non-coding developmental regulatory RNA; FXR, farnesoid X receptor; GAS5, growth arrest-specific transcript 5; H3K18ac, histone 3 lysine 18 acetylation; H3K36me3, histone 3 lysine 36 trimethylation; H3K4me3, histone 3 lysine 4 trimethylation; HCC, hepatocellular carcinoma; HEIH, high expression In HCC; HNRNPA1, heterogenous nuclear protein ribonucleoprotein A1; HOTAIR, HOX transcript antisense RNA; HOTTIP, HOXA transcript at the distal tip; HSC, hepatic stellate cells; HULC, highly upregulated in liver cancer; Hepatocellular carcinoma; HuR, human antigen R; LCSC, liver cancer stem cell; LSD1, lysine-specific demethylase 1; LXR, liver X receptors; LeXis, liver-expressed LXR-induced sequence; Liver cancer; Liver fibrosis; Liver metabolism; Liver-specific lncRNAs; LncLSTR, lncRNA liver-specific triglyceride regulator; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; MEG3, maternally expressed gene 3; NAT, natural antisense transcript; NEAT1, nuclear enriched abundant transcript 1; ORF, open reading frame; PKM2, pyruvate kinase muscle isozyme M2; PPAR-α, peroxisome proliferator-activated receptor-α; PRC, polycomb repressive complex; RACE, rapid amplification of cDNA ends; RNA Pol, RNA polymerase; S6K1, S6 kinase 1; SHP, small heterodimer partner; SREBPs, steroid response binding proteins; SREs, sterol response elements; TGF-β, transforming growth factor-β; TTR, transthyretin; XIST, X-inactive specific transcript; ZEB1, zinc finger E-box-binding homeobox 1; ceRNA, competing endogenous RNA; eRNA, enhancer RNAs; lincRNA, long intervening non-coding RNA; lncRNA; lncRNA, long non-coding RNA; mTOR, mammalian target of rapamycin; siRNA, small interfering RNA.

Fig. 1

Quantifications of lncRNA genes and their transcripts in multiple species as deposited in the release of NONCODE v.5 database. Transcripts consider the number of lncRNA isoforms identified for each lncRNA gene.

Fig. 2

LncRNAs are classified by genomic origins relative to protein-coding genes. Divergent lncRNAs are encoded on the opposite strand and direction from protein-coding genes. As the name suggests, lincRNAs are found in regions between genes. NATs are transcribed from the antisense strand of a protein-coding gene. 1D-eRNAs are lncRNAs transcribed from regions identified as enhancers and are distinct from 2D-eRNAs, which are divergently transcribed and non-polyadenylated transcripts produced from enhancers. eRNA, enhancer RNA; lincRNA, long intervening non-coding RNA; lncRNA, long non-coding RNA; NATs, natural antisense transcripts; TSS, transcription start site.

Fig. 3

LncRNAs regulate various aspects of lipid metabolism. Extrahepatic cholesterol enters hepatocytes through the LDL receptor (LDLR). lncRNAs lnc-HC and lncLSTR control key enzymes in cholesterol catabolism. H19 and MALAT1 regulate SREBP-1c stability. SREBP-1c controls the expression of genes regulating fatty acid synthesis including ACLY (ATP citrate synthase), ACC (acetyl-CoA carboxylase), FASN (fatty acid synthase) and ELOVL1 (ELOVL fatty acid elongase 1). HNF4α, which regulates critical genes such as PEPCK in gluconeogenesis, is inhibited by H19. Changes in the ratio of bile acids triggers FXR activation as a transcription factor to promote the expression of APOC2. Lipoproteins including APOA1 and APOA4 are involved in transfer of lipid molecules and are regulated by APOA1-AS and APOA4-AS. ER, endoplasmic reticulum.

Fig. 4

An overview of lncRNAs involved in liver development, metabolism and disease. LncRNAs implicated in hepatocellular carcinoma are classified based on whether they act as oncogenes or tumour suppressor genes (TSG).