Table 1.

Potential targets of lncRNA H19 in cholestatic liver fibrosis

Animal models or Human Samples	In vitro models	Targets	Effects	Ref # (Year)
C57BL/6 & H19−/− mice. 2-week BDL	HepG2, Huh7, Hep3B, H69, Mz-Cha-1, CCLP-1, HuCCT1, SG231. Mouse Hepa1, MLC, and MSC.	ZEB1 EpCAM SOX9	BDL-induced H19 suppressed ZEB1 expression, which resulted in the de-repression of EpCAM by ZEB1 and cholestatic liver fibrosis.	(32)(2017)
C57 male mice 3 and 4-week CCl4	Primary mouse hepatocytes, AML12 cell line	Sox9	Sox9-mediated upregulation of H19 is responsible for CCl4-induced liver fibrosis.	(5)(2017)
Sprague-Dawley male rats, 12-week CCl4 model	HSC-T6 cell line	DNMT1 ERK	DNMT1-mediated epigenetic regulation of H19 and H19-mediated activation. ERK1/2 promoted HSC activation and liver fibrosis	(38)(2018)
Mdr2−/−, H19−/− (Δ Exon1/+) PSC liver samples (n=16) 8-week CCL4 mouse model	Primary mouse hepatocytes, cholangiocytes, and Kupffer cells; MLC cell line	FXR/SHP S1PR2/ERK1/2	Bile acid/estrogen-induced H19 expression in cholangiocytes is responsible for gender disparity of cholestatic liver injury in Mdr2−/− mice by downregulation of SHP and activation of S1PR2 /ERK1/2 signaling pathways.	(16, 29)(2017, 2018)
C57/BL6 male mice 8-week CCl4 mouse model	Primary mouse HSCs, human LX2 and L02 cell lines	miR148a, USP4 TGF-β/SMAD	H19 promoted hepatic fibrosis by activating HSCs via sponging miR148a and upregulating USP4, which enhanced the TGF-β-mediated activation of SMAD in HSCs.	(37)(2018)
C57/BL6 Mdr2−/−, H19−/− (Δ Exon1/+) and DKO mice; 2-week BDL model	Primary mouse hepatocytes, HSCs, cholangiocytes, and Kupffer cells; MLC, H69 and LX2 cell lines	CyclinD1/p21 CCL2/CCR2	Cholangiocyte-derived exosomal H19 is preferentially taken up by HSCs and Kupffer cells significantly promoted the activation of HSCs and macrophages in liver fibrotic progression.	(30,31)(2019, 2020)
C57/BL6 male mice BDL for 2, 4, and 6 weeks.	JS-1 murine HSC cell line	PI3K/AKT/mTOR	H19 promoted autophagy by interacting with the PI3K/AKT/mTOR pathway, which was responsible for IGFBPrP1-induced activation of HSC and liver fibrosis.	(39)(2019)
Human BA patient liver samples (n=57) Mdr2−/−, H19−/− and DKO 2-week BDL model	MLC cell line HUCCT1	S1PR2 Let7/HMGA2	H19 expression level is correlated to disease severity in BA patients. H19 promotes cholangiocyte proliferation and fibrotic liver injury by regulating S1PR2 and let-7/ HMGA2–mediated pathways.	(35)(2019)
ICR male mice 8-week CCl4 mouse model	Primary mouse HSCs and human LX2 cell lines	ADH3/ALDH1 RARα/RXRβ AMPKα/LKB1	H19 induced HSC activation by upregulation of ADH3/ALDH1 and retinoic acid signaling pathways and by activation of AMPKα via facilitating the formation of AMPKα/LKB1 complex.	(33,34)(2020)
C57/BL6j H19−/−male mice 1-week BDL model	Human Huh7, Mouse Hepa1, MSC, and MLC cell lines	PTBP1 and Let7	H19 suppressed the expression of PTBP1, which inhibited the biogenesis of Let7, but enhanced the bioavailability to their targets.	(36)(2020)