PhD Scientific Days 2025

Molecular Medicine IV.

Crosstalk of LKB1- and PKA-dependent signaling pathways in the regulation of hepatocyte polarity

Name of the presenter

Körmendi Petra

Institute/workplace of the presenter

HUN-REN Research Centre for Natural Sciences

Authors

Petra Körmendi¹, Ágnes Telbisz¹, Anikó Zeöld², László Homolya¹

1: HUN-REN Research Centre for Natural Sciences
2: Semmelweis University

Text of the abstract

Cell polarization is an essential part of the development of a functional liver cell. The bile canaliculi begin to form on the apical side of two adjacent liver cells, then interconnect and develop into a canalicular network. The presence of a functional canalicular network is essential for most hepatic functions including bile secretion, cholesterol metabolism, detoxification, etc. Disruption of canalicular secretion can cause intrahepatic cholestasis by bile salt accumulation, which can lead to inflammation, fibrosis, or even liver failure. Hepatocyte polarization and its regulation are therefore of great medical importance.
The key role of tumor-suppressor liver kinase B1 (LKB1) in hepatocyte polarization has long been known. Bile acids, such as taurocholate (TC), stimulate canalicular network formation via LKB1/AMPK-dependent signaling pathway. We have previously shown an essential role for LKB1 in the regulation of polarized trafficking of canalicular membrane proteins and have also revealed the existence of a collateral PKA-dependent signaling pathway. In the present work, we investigated whether PKA also influences canalicular network formation and whether there is a crosstalk between the two pathways. For this purpose, we monitored the in vitro repolarization process of the human hepatic model HepaRG cells and isolated rat primary hepatocytes by Western blot analysis and immunofluorescence microscopy. The cells were treated with TC, the cAMP-elevating agent forskolin, and the PKA activator 6-benzoyl-cAMP (6Bnz). Our results showed that specific activation of PKA stimulates canalicular network formation and demonstrated a crosstalk between the two signaling pathways: activation of PKA leads to phosphorylation of LKB1 and stimulation of downstream processes, such as development of bile canaliculi. LKB1 knockdown experiments clearly demonstrated the LKB1-dependence of this stimulation. Our results may help to understand the molecular mechanisms responsible for the pathogenesis of diseases involving hepatocyte polarity and thus help to identify novel therapeutic targets for the treatment of liver diseases.
This work has been supported by the National Research, Development and Innovation Office (grant number: OKTA K-128123)