The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice

Abstract

The multi-drug resistance 2 knockout (Mdr2−/−) mouse is a well-established model of cholestatic cholangiopathies. Female Mdr2−/− mice develop more severe hepatobiliary damage than male Mdr2−/− mice, which is correlated with a higher proportion of taurocholate (TCA) in bile. Although estrogen has been identified as an important player in intrahepatic cholestasis, the underlying molecular mechanisms of gender-based disparity of cholestatic injury remain unclear. The long non-coding RNA H19 is an imprinted, maternally expressed and estrogen-targeted gene, which is significantly induced in human fibrotic/cirrhotic liver and bile duct ligated mouse liver. However, whether aberrant expression of H19 accounts for gender-based disparity of cholestatic injury in Mdr2−/− mice remains unknown. The current study demonstrated that H19 was markedly induced (~200-fold) in the livers of female Mdr2−/− mice at advanced stages of cholestasis (100-day-old), but not in aged-matched male Mdr2−/− mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that the hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both TCA and estrogen significantly activated the ERK1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced TCA/estrogen-induced expression of fibrotic genes and sphingosine 1-phosphate receptor 2 (S1PR2) in cholangiocytes, but also markedly reduced cholestatic injury in female Mdr2−/− mice. Furthermore, the expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 shRNA in female Mdr2−/− mice. Similar findings were obtained in human PSC liver samples. Conclusion H19 plays a critical role in the disease progression of cholestasis and represents a key factor that causes the gender disparity of cholestatic liver injury in Mdr2−/− mice.

lncRNA SNHG5 is associated with poor prognosis of bladder cancer and promotes bladder cancer cell proliferation through targeting p27

“…Accumulating documents have revealed that lncRNAs play a critical role in tumorigenesis and can be used as biomarkers for diagnosis or prediction of survival and recurrence in multiple cancers (5)(6)(7)(8)(9). For instance, in 2017, Idogawa et al reported that long non-coding RNA NEAT1 was a transcriptional target of p53 and modulated p53-induced transactivation and tumor-suppressor function (10).…”

H19 Is Expressed in Hybrid Hepatocyte Nuclear Factor 4α+ Periportal Hepatocytes but Not Cytokeratin 19+ Cholangiocytes in Cholestatic Livers

“…Indeed, discrepant results have been reported. H19 RNA was highly expressed in isolated hepatocytes at day 3 after PH in one study, whereas another study reported that H19 RNA was mainly expressed in primary cholangiocytes and was not expressed in hepatocytes or Kupffer cells . There is an urgent need to develop a new method to precisely localize the subcellular distribution of H19, especially in human liver specimens.…”

Long non-coding RNA in liver metabolism and disease: Current status

“…H19 was shown to be representing a key factor that causes the gender disparity of cholestatic liver injury not only in Mdr2 KO mice, and probably in human PSC patients. 4 …”

“…3 Extensive studies have been conducted on miRNAs, however the functions of lncRNAs remain poorly understood. 4,5 Recent studies have revealed that lncRNAs significantly impact on various biological processes as X-inactivation, genomic imprinting, chromatin modification, cell fate specification, cell apoptosis, nuclear trafficking, and genome rearrangement. 6 …”