Hippo signalling in the liver: role in development, regeneration and disease

Abstract

The Hippo signalling pathway has emerged as a major player in many aspects of liver biology, such as development, cell fate determination, homeostatic function and regeneration from injury. The regulation of Hippo signalling is complex, with activation of the pathway by diverse upstream inputs including signals from cellular adhesion, mechanotransduction and crosstalk with other signalling pathways. Pathological activation of the downstream transcriptional co-activators yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, encoded by WWTR1), which are negatively regulated by Hippo signalling, has been implicated in multiple aspects of chronic liver disease, such as the development of liver fibrosis and tumorigenesis. Thus, development of pharmacological inhibitors of YAP-TAZ signalling has been an area of great interest. In this Review, we summarize the diverse roles of Hippo signalling in liver biology and highlight areas where outstanding questions remain to be investigated. Greater understanding of the mechanisms of Hippo signalling in liver function should help facilitate the development of novel therapies for the treatment of liver disease.

Figure 1). Hippo signaling pathway.

a) The Hippo signaling pathway functions to repress activity of the transcriptional co-activators YAP and TAZ. The kinases MST1/2 form a complex with the scaffolding protein SAV1 and phosphorylate the kinases LATS1/2 in a manner facilitated by NF2. Together with the regulatory proteins MOB1A/B, LATS1/2 phosphorylate YAP/TAZ, which are bound by 14-3-3 and targeted for proteasomal degradation by β-TRCP. Other inputs such as LKB1 or GPCR signaling or contact inhibition through adherens junctions can suppress YAP/TAZ activity. b) Multiple upstream inputs such as stiff ECM, low cell density, bile acid exposure, GPCR signaling, and increased actomyosin tension can inhibit Hippo signaling. Non-phosphorylated YAP/TAZ are no longer targeted for degradation and translocate to the nucleus where they interact with TEAD transcription factors to promote target gene expression.

Figure 2). Role of Hippo signaling in liver development.

a) During mouse embryonic development, hepatic specification occurs at E8.25. Interactions of the foregut endoderm with the septum transversum and cardiac mesoderm are required for the specification of hepatic endoderm. b) Hepatoblasts, the embryonic precursors to hepatocytes and cholangiocytes, first appear in the liver bud at E9. c) Hepatoblast differentiation to hepatocytes or cholangiocytes occurs between E11.5 – E15.5. Cholangiocyte differentiation requires Wnt, TGFβ, and Notch signaling, while hepatocyte differentiation requires a regulatory network of transcription factors. d) Liver maturation continues after birth to form the mature hepatic architecture. e) Deletion of Yap1 via Albumin-Cre impairs bile duct formation and reduces hepatocyte viability. f) Hyperactivation of YAP through deletion of upstream Hippo components via Albumin-Cre results in failure to form mature hepatocytes and expansion of immature biliary cells.

Figure 3). Role of Hippo signaling in liver homeostasis and regeneration.

a) Architecture of the hepatic lobule during homeostasis. The portal triad consists of the portal vein, hepatic artery, and bile ducts. Blood from the portal vein flows through the hepatic sinusoids lined by liver sinusoidal endothelial cells (LSECs) to the central vein. The sinusoids are lined by chords of hepatocytes. Hepatic stellate cells (HSCs) reside in the space of Disse (between LSECs and hepatocytes). During homeostasis YAP is active in a subset of BECs within the bile ducts. b) After surgical resection of liver tissue, such as during PHx, YAP signaling is activated in HSCs and hepatocytes. c) BEC injury, such as administration of the DDC diet, triggers the ductular reaction. YAP activity in increased in BECs and a subset of hepatocytes. YAP activity in hepatocytes may trigger transdifferentiation to BECs. d) Injury induced by CCl₄ administration leads to YAP activation in HSCs and promotes collagen deposition and the development of liver fibrosis.

Figure 4). Role of Hippo signaling in liver cancer.

a) In HCC, factors such as rigid ECM, bile acid exposure, hypoxia, and increased actomyosin tension can trigger YAP activation. YAP can promote tumorigenesis through increased nucleotide biosynthesis, enhanced Notch signaling, and expression of amino acid transporters. β-catenin inhibits YAP activity through inhibition of Notch signaling. b) In hepatoblastoma, β-catenin and YAP cooperate to promote tumorigenesis through expression of amino acid transporter SLC38A1. Increased accumulation of amino acids activates mTORC1 signaling to promote tumorigenesis. c) In cholangiocarcinoma, AKT and YAP can cooperate to enhance Notch signaling, which in turn promotes BEC differentiation and tumorigenesis. The inflammatory cytokines IL6 and IL33 promote this process.

Figure 5). Strategies for targeting the Hippo signaling pathway.

a) Strategies to suppress liver cancer by inhibiting YAP activity in tumor cells. b) Strategies to promote liver regeneration by augmenting YAP activity in hepatocytes and to inhibit fibrosis progression by specifically inhibiting YAP activity in HSCs.