Z Gastroenterol 2020; 58(01): e8-e9
DOI: 10.1055/s-0039-3402120
Poster Visit Session I Basic Hepatology (Fibrogenesis, NPC, Transport): Friday, February 14, 2020, 12:30 pm – 1:15 pm, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

Hippo pathway effectors YAP and TAZ are opponents in the regulation of hepatic fibrosis

K Liu
1   Heidelberg university, Institute of Pathology, Heidelberg, Germany
,
M Tóth
1   Heidelberg university, Institute of Pathology, Heidelberg, Germany
,
T Guo
2   German Cancer Research Center (DKFZ), Divison of Signal Transduction and Growth Control, Heidelberg, Germany
,
F Rose
1   Heidelberg university, Institute of Pathology, Heidelberg, Germany
,
SME Weiler
1   Heidelberg university, Institute of Pathology, Heidelberg, Germany
,
S Wan
3   Soochow University, Faculty of bioscience and basic medical science, Department of Pathology, Suzhou, China
,
M Heikenwälder
4   German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Heidelberg, Germany
,
P Schirmacher
1   Heidelberg university, Institute of Pathology, Heidelberg, Germany
,
T Longerich
1   Heidelberg university, Institute of Pathology, Heidelberg, Germany
,
K Breuhahn
1   Heidelberg university, Institute of Pathology, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

Also available at
 

Question:

Paracrine cross-talk between liver-resident cells affects the development and progression of fibrosis. For example, overexpression of the transcriptional co-activator yes-associated protein (YAP) in hepatocytes supports deposition of extracellular material of hepatic stellate cells. We therefore asked, if silencing of hepatocellular YAP and its paralogue WW domain containing transcription regulator 1 (WWTR1; syn: TAZ) may represent a reasonable approach to reduce liver fibrosis.

Methods:

As model, we systematically characterized mice with hepatocyte-specific inactivation of YAP (YAPKO), TAZ (TAZKO) as well as YAP/TAZ (YAPKO/TAZKO) and induced liver fibrosis by intraperitoneal injection of carbon tetrachloride (CCl4; 2x/week for 6 weeks).

Results:

Serum derived from unchallenged YAPKO and YAPKO/TAZKO, but not from wildtype and TAZKO animals, showed markedly higher levels of liver damage markers (ALT: up to 792 U/L; AST: up to 867 U/L). Interestingly, automated whole slide analysis after Sirius red staining revealed the development of severe fibrosis in YAPKO livers, which was less pronounced in animals with combined YAP/TAZ silencing. Four weeks after the last CCl4 injection, ALT and AST of YAPKO and YAPKO/TAZKO mice were still elevated, while in wildtype and TAZKO mice both liver damage makers normalized. Importantly, compared to YAPKO mice, AST/ALT levels were significantly lower in YAPKO/TAZKO animals. Livers derived from CCl4-treated YAPKO mice showed significantly elevated liver fibrosis compared to untreated YAPKO animals, while the simultaneous silencing of YAP/TAZ partly abolished this phenotype (automated picture analysis and Ishak score). Histologically, CCl4 treatment caused clear bridging fibrous septa in wildtype and TAZKO mice. In contrast, YAP-deficiency led to the formation of profound diffuse septal liver fibrosis. Again, this phenotype was dampened in samples derived from YAPKO/TAZKO mice.

Conclusions:

These data illustrate that hepatocellular YAP activity is key for the maintenance of liver organization and extracellular material deposition. Its perturbation does not present a reasonable approach to block liver fibrosis since YAP-deficiency is sufficient to cause fibrosis. In this regard, YAP and TAZ have different functions in fibrosis. While YAP-deficiency aggravates fibrogenesis, TAZ-deficiency alone plays as protective and dampens the effects observed after YAP-silencing.