Journal
JOURNAL OF HEPATOLOGY
Volume 71, Issue 1, Pages 130-142Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2019.02.022
Keywords
Mechanotransduction; Capping protein; CAPZ; F-actin dynamics; YAP; Hippo; Organ growth; Hepatocyte cell fate maintenance; Glucose metabolism; Gluconeogenesis; Xenobiotic metabolism; Liver homeostasis
Categories
Funding
- AIRC (Fondazione AIRC per la Ricerca sul Cancro) Investigator Grants [15307, 21392]
- WCR (Worldwide Cancer Research) Grant [15-1192]
- CARIPARO Eccellenza Program 2017
- University of Padua BIRD Grant
- AIRC 'Hard ROCK Cafe' Fellowship
- Marie Sklodowska-Curie Individual Fellowship [796547]
- AIRC Special Program Molecular Clinical Oncology '5 per mille' [10016]
- UK Medical Research Council
- Sackler Foundation Doctoral Training Grant [RG70550]
- UK Medical Research Council Career Development Award [G1100312/1]
- Isaac Newton Trust Research Grant [17.24]
- MRC [G1100312] Funding Source: UKRI
- Marie Curie Actions (MSCA) [796547] Funding Source: Marie Curie Actions (MSCA)
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Background & Aims: In vitro, cell function can be potently regulated by the mechanical properties of cells and of their microenvironment. Cells measure these features by developing forces via their actomyosin cytoskeleton, and respond accordingly by regulating intracellular pathways, including the transcriptional coactivators YAP/TAZ. Whether mechanical cues are relevant for in vivo regulation of adult organ homeostasis, and whether this occurs through YAP/TAZ, remains largely unaddressed. Methods: We developed Capzb conditional knockout mice and obtained primary fibroblasts to characterize the role of CAPZ in vitro. In vivo functional analyses were carried out by inducing Capzb inactivation in adult hepatocytes, manipulating YAP/Hippo activity by hydrodynamic tail vein injections, and treating mice with the ROCK inhibitor, fasudil. Results: We found that the F-actin capping protein CAPZ restrains actomyosin contractility: Capzb inactivation alters stress fiber and focal adhesion dynamics leading to enhanced myosin activity, increased traction forces, and increased liver stiffness. In vitro, this rescues YAP from inhibition by a small cellular geometry; in vivo, it induces YAP activation in parallel to the Hippo pathway, causing extensive hepatocyte proliferation and leading to striking organ overgrowth. Moreover, Capzb is required for the maintenance of the differentiated hepatocyte state, for metabolic zonation, and for gluconeogenesis. In keeping with changes in tissue mechanics, inhibition of the contractility regulator ROCK, or deletion of the Yap1 mechanotransducer, reverse the phenotypes emerging in Capzb-null livers. Conclusions: These results indicate a previously unsuspected role for CAPZ in tuning the mechanical properties of cells and tissues, which is required in hepatocytes for the maintenance of the differentiated state and to regulate organ size. More generally, it indicates for the first time that mechanotransduction has a physiological role in maintaining liver homeostasis in mammals. Lay summary: The mechanical properties of cells and tissues (i.e. whether they are soft or stiff) are thought to be important regulators of cell behavior. Herein, we found that inactivation of the protein CAPZ alters the mechanical properties of cells and liver tissues, leading to YAP hyperactivation. In turn, this profoundly alters liver physiology, causing organ overgrowth, defects in liver cell differentiation and metabolism. These results reveal a previously uncharacterized role for mechanical signals in the maintenance of adult liver homeostasis. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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