title: The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice.
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.
  
  
  
  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).
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.|Department of Microbiology and Immunology, Virginia Commonwealth University, and McGuire Veterans Affairs Medical Center, Richmond, VA.
authors.forename: Xiaojiaoyang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, and McGuire Veterans Affairs Medical Center, Richmond, VA.|Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Runping
authors.initials: R
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.|Department of Microbiology and Immunology, Virginia Commonwealth University, and McGuire Veterans Affairs Medical Center, Richmond, VA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.|Department of Microbiology and Immunology, Virginia Commonwealth University, and McGuire Veterans Affairs Medical Center, Richmond, VA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.|Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Puneet
authors.initials: P
authors.lastname: Puri
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, and McGuire Veterans Affairs Medical Center, Richmond, VA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Gurley
authors.affiliation: Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Lai
authors.affiliation: Jiangsu Collaborative Innovation Center of Chinese Medicinal Resource Industrialization and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, and McGuire Veterans Affairs Medical Center, Richmond, VA.|Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, and McGuire Veterans Affairs Medical Center, Richmond, VA.|Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, and McGuire Veterans Affairs Medical Center, Richmond, VA.|Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA.|Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Huiping
authors.identifier: 0000-0002-0050-372X
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D015209:Cholangitis, Sclerosing / Q000235:genetics / Q000473:pathology*; D002779:Cholestasis / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D019450:Genes, MDR; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics*; D049349:Receptors, Lysosphingolipid / Q000235:genetics*; D012380:Role; D012737:Sex Factors; D000081025:Sphingosine-1-Phosphate Receptors; D013656:Taurocholic Acid / Q000494:pharmacology
chemical_list: D004967:Estrogens; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; D013656:Taurocholic Acid; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1