The Hippo Pathway in Liver Homeostasis and Pathophysiology

Abstract

Studies of the regenerative capacity of the liver have converged on the Hippo pathway, a serine/threonine kinase cascade discovered in Drosophila and conserved from unicellular organisms to mammals. Genetic studies of mouse and rat livers have revealed that the Hippo pathway is a key regulator of liver size, regeneration, development, metabolism, and homeostasis and that perturbations in the Hippo pathway can lead to the development of common liver diseases, such as fatty liver disease and liver cancer. In turn, pharmacological targeting of the Hippo pathway may be utilized to boost regeneration and to prevent the development and progression of liver diseases. We review current insights provided by the Hippo pathway into liver pathophysiology. Furthermore, we present a path forward for future studies to understand how newly identified components of the Hippo pathway may control liver physiology and how the Hippo pathway is regulated in the liver.

Keywords: Hippo pathway; YAP/TAZ; fatty liver disease; liver cancer; metabolism; regeneration.

Figure 1

The Hippo pathway in mammals. Components in red denote the core proteins of the Hippo pathway, and components within the dotted rectangle indicate components of the canonical kinase cascade. Components in green are regulators of the Hippo pathway that are important in the liver, and components in blue denote regulators identified in Drosophila or in mammals that have not yet been tested in the liver but are discussed in this review.

Figure 2

Cell-type-specific functions of the Hippo pathway. The Hippo pathway and YAP/TAZ play key roles in hepatocytes, cholangiocytes, endothelial cells, and stellate cells within the liver, which are depicted here in a representation of a hepatic lobule. Shared features include that YAP/TAZ regulate liver regeneration in the context of the stellate cell, hepatocyte, and cholangiocyte and are involved in cancers that originate from liver bile duct cells, hepatocytes, and endothelial cells.

Figure 3

Regulation of the Hippo pathway. (a) Summary of inputs and outputs of the Hippo pathway that converge on YAP/TAZ. Schematics of regulation of the Hippo pathway by (b) energy levels and AMPK, (c) high glucose, (d) the mevalonate pathway, (e) bile acids, (f) GPCRs and their ligands, and (g) mechanical forces. Components in red denote the core proteins of the Hippo pathway, and components in green are regulators of the Hippo pathway that are important in the liver. Blue components denote regulators identified in Drosophila or in mammals that have not yet been tested in the liver but are discussed in this review.