Back to Search
Start Over
The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice
- Source :
- Hepatology. 66:869-884
- Publication Year :
- 2017
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2017.
-
Abstract
- The multidrug 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 in the 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 noncoding 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 days old) but not in age-matched male Mdr2-/- mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both taurocholate and estrogen significantly activated the extracellular signal-regulated kinase 1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced taurocholate/estrogen-induced expression of fibrotic genes and sphingosine 1-phosphate receptor 2 in cholangiocytes but also markedly reduced cholestatic injury in female Mdr2-/- mice. Furthermore, expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 short hairpin RNA in female Mdr2-/- mice. Similar findings were obtained in human primary sclerosing cholangitis 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. (Hepatology 2017;66:869-884).
- Subjects :
- Liver Cirrhosis
Male
Taurocholic Acid
0301 basic medicine
medicine.medical_specialty
Cholangitis, Sclerosing
Down-Regulation
Biology
Cholangiocyte
Primary sclerosing cholangitis
Small hairpin RNA
Gene Knockout Techniques
Mice
03 medical and health sciences
Sex Factors
Cholestasis
Internal medicine
medicine
Animals
Humans
Sphingosine-1-Phosphate Receptors
Gene knockout
Mice, Knockout
Mitogen-Activated Protein Kinase 1
Liver injury
Hepatology
Role
Estrogens
medicine.disease
Disease Models, Animal
Receptors, Lysosphingolipid
030104 developmental biology
Endocrinology
Gene Expression Regulation
Small heterodimer partner
Female
RNA, Long Noncoding
Genes, MDR
Subjects
Details
- ISSN :
- 15273350 and 02709139
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi.dedup.....bb9c79695f5f82400f3913526fbc0f2e