Amino acid-induced regulation of hepatocyte growth: possible role of Drosha

Gaia Fabris,Didier F Pisani,Emmanuel Van Obberghen,Nadine Gautier,Olivier Dumortier

doi:10.1038/s41419-019-1779-7

Abstract

In an adult healthy liver, hepatocytes are in a quiescent stage unless a physical injury, such as ablation, or a toxic attack occur. Indeed, to maintain their crucial organismal homeostatic role, the damaged or remaining hepatocytes will start proliferating to restore their functional mass. One of the limiting conditions for cell proliferation is amino-acid availability, necessary both for the synthesis of proteins important for cell growth and division, and for the activation of the mTOR pathway, known for its considerable role in the regulation of cell proliferation. The overarching aim of our present work was to investigate the role of amino acids in the regulation of the switch between quiescence and growth of adult hepatocytes. To do so we used non-confluent primary adult rat hepatocytes as a model of partially ablated liver. We discovered that the absence of amino acids induces in primary rat hepatocytes the entrance in a quiescence state together with an increase in Drosha protein, which does not involve the mTOR pathway. Conversely, Drosha knockdown allows the hepatocytes, quiescent after amino-acid deprivation, to proliferate again. Further, hepatocyte proliferation appears to be independent of miRNAs, the canonical downstream partners of Drosha. Taken together, our observations reveal an intriguing non-canonical action of Drosha in the control of growth regulation of adult hepatocytes responding to a nutritional strain, and they may help to design novel preventive and/or therapeutic approaches for hepatic failure.

Highlights

The liver is one of the eminently important organs in the regulation of organismal homeostasis in vertebrates, as it exerts and orchestrates multiple essential biological functions, including all fuel metabolism, detoxification of intrinsic and extrinsic substances and production of numerous proteins with diverse extra-hepatic actions
To investigate the effect of total aa deprivation on primary adult rat hepatocytes, we cultured them in aa presence or absence
The aa-deprived hepatocyte population appears to be more stable after 48 h, as their number decreases slower compared to hepatocytes in complete Dulbecco’s Modified Eagle Medium (DMEM)

Summary

Introduction

The liver is one of the eminently important organs in the regulation of organismal homeostasis in vertebrates, as it exerts and orchestrates multiple essential biological functions, including all fuel metabolism, detoxification of intrinsic and extrinsic substances and production of numerous proteins with diverse extra-hepatic actions. Proteins, representing ~15% of body mass in healthy adults[1], have major roles as constituents of all cells, and as molecules enabling cells to function, grow, and differentiate. Fabris et al Cell Death and Disease (2019)10:566 protein synthesis, has an essential role in regulating cell proliferation through the activation of mTOR and its downstream S6 kinase[11,12]. By using non-confluent primary adult rat hepatocytes, we mimicked the condition of active proliferation after an injury, being able to investigate the regulation of hepatocyte growth capacity by aa. Our findings unveil a newly identified non-canonical role of Drosha in regulating the response of adult hepatocytes to aa availability and could contribute to innovative approaches to prevent and/or treat hepatic failure

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