The overarching goal of this proposal is to investigate the Hippo signaling pathway in the liver and how it contributes to the pathogenesis of hepatic fibrosis. The outcome of these studies will impact on our understanding of hepatic development and recovery after injury. The Hippo signaling pathway is an important regulator of liver size, cellular proliferation and cell fate. The Hippo pathway negatively regulates Yap. High levels of Yap in hepatocytes convert these cells into a hepatic progenitor cell (HPC)-like phenotype. Rapidly dividing HPCs are associated with the development of fibrosis, and it is known that Yap directly activates genes associated with this process. Cirrhotic liver samples often display nuclear Yap staining (a sign of Hippo inactivation) and hepatic stellate cell (HSC) activation is temporally associated with increasing Yap. These observations suggest that inactivating Hippo signaling in epithelial cells can activate a profibrotic gene program. This proposal will validate and dissect the mechanism of this observation.
In AIM 1, several fibrogenic liver injury models will be examined to see if Hippo signaling is inactivated. This will be complemented with loss of function studies in the epithelial compartment to determine if abrogating Hippo signaling will minimize the development of fibrosis.
In AIM 2, Yap-expressing hepatocytes will be examined by cellular fractionation and using single-cell sequencing techniques to determine if a priori, a particular hepatocyte type is most sensitive to Yap expression and if this cell-type likely orchestrates the development of liver fibrosis.
AIM 3, focuses on determining which secreted factors from Yap-expressing hepatocytes likely activate HSCs. This will be performed using RNA interference and Cas9-Crispr technologies to knockdown expression of candidate molecules defined by microarray expression and ChIP-Seq data from Yap overexpressing hepatocytes. This screen will be performed in vitro followed by in vivo validation. Understanding if Hippo signaling is a common mechanism for the development of hepatic fibrosis, the characteristics of the epithelial cells that may orchestrate this process, and potential secreted factors to activate HSCs will be important information in developing therapeutics to treat liver fibrosis.

Public Health Relevance

During liver regeneration, balancing the renewal of cells with metabolic and detoxifying activities with their supporting cells must be accomplished to generate normal organs. Hippo signaling tightly regulates cell division in the liver, but also appears to control signals that activates fibrosis, or scarring of the liver. This study, proposes to investigte if the Hippo pathway is a crucial mediator of liver fibrosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Boston
United States
Zip Code
Leung, Daniel H; Yimlamai, Dean (2017) The intestinal microbiome and paediatric liver disease. Lancet Gastroenterol Hepatol 2:446-455
Patel, Sachin H; Camargo, Fernando D; Yimlamai, Dean (2017) Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, andĀ Carcinogenesis. Gastroenterology 152:533-545
Cox, Andrew G; Hwang, Katie L; Brown, Kristin K et al. (2016) Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat Cell Biol 18:886-896
Yimlamai, Dean; Fowl, Brendan H; Camargo, Fernando D (2015) Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J Hepatol 63:1491-501
Yimlamai, Dean; Christodoulou, Constantina; Galli, Giorgio G et al. (2014) Hippo pathway activity influences liver cell fate. Cell 157:1324-38
Ganem, Neil J; Cornils, Hauke; Chiu, Shang-Yi et al. (2014) Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell 158:833-848
Tumaneng, Karen; Schlegelmilch, Karin; Russell, Ryan C et al. (2012) YAP mediates crosstalk between the Hippo and PI(3)Kā€“TOR pathways by suppressing PTEN via miR-29. Nat Cell Biol 14:1322-9