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- Title
Elimination of Wnt Secretion From Stellate Cells Is Dispensable for Zonation and Development of Liver Fibrosis Following Hepatobiliary Injury.
- Authors
Rong Zhang; Kikuchi, Alexander T.; Toshimasa Nakao; Russell, Jacquelyn O.; Preziosi, Morgan E.; Poddar, Minakshi; Sucha Singh; Bell, Aaron W.; England, Steven G.; Monga, Satdarshan P.
- Abstract
Alterations in the Wnt signaling pathway including those impacting hepatic stellate cells (HSCs) have been implicated in liver fibrosis. In the current study, we first examined the expression of Wnt genes in human HSC (HHSCs) after treatment with a profibrogenic factor TGF-b1. Next, we generated HSC-specific Wntless (Wls) knockout (KO) using the Lrat-cre and Wls-floxed mice. KO and littermate controls (CON) were characterized for any basal phenotype and subjected to two liver fibrosis protocols. In vitro, TGF-b1 induced expression of Wnt2, 5a and 9a while decreasing Wnt2b, 3a, 4, and 11 in HHSC. In vivo, KO and CON mice were born at normal Mendelian ratio and lacked any overt phenotype. Loss of Wnt secretion from HSCs had no effect on liver weight and did not impact b-catenin activation in the pericentral hepatocytes. After 7 days of bile duct ligation (BDL), KO and CON showed comparable levels of serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total and direct bilirubin. Comparable histology, Sirius red staining, and immunohistochemistry for a-SMA, desmin, Ki-67, F4/80, and CD45 indicated similar proliferation, inflammation, and portal fibrosis in both groups. Biweekly administration of carbon tetrachloride for 4 or 8 weeks also led to comparable serum biochemistry, inflammation, and fibrosis in KO and CON. Specific Wnt genes were altered in HHSCs in response to TGF-b1; however, eliminating Wnt secretion from HSC did not impact basal b-catenin activation in normal liver nor did it alter the injury--repair response during development of liver fibrosis.
- Subjects
WNT signal transduction; LIVER disease treatment; LIVER cells; TRANSFORMING growth factor-beta induced protein; WNT genes
- Publication
Gene Expression (1052-2166), 2019, Vol 19, Issue 2, p121
- ISSN
1052-2166
- Publication type
Article
- DOI
10.3727/105221618X15373858350141