Retinoids Issued from Hepatic Stellate Cell Lipid Droplet Loss as Potential Signaling Molecules Orchestrating a Multicellular Liver Injury Response

Abstract

Hepatic stellate cells (HSCs) serve as the main body storage compartment for vitamin A through retinyl ester (RE)-filled lipid droplets (LDs). Upon liver injury, HSCs adopt a myofibroblastic phenotype characterized by an elevated expression of extracellular matrix proteins and a concomitant loss of LDs. On the one hand, LD breakdown has been suggested to provide the energy required for HSC activation into myofibroblast-like cells. On the other hand, this process could mitigate HSC activation following the transformation of released REs into retinoic acids (RAs), ligands for nuclear receptors exerting antifibrotic transcriptional regulatory activities in HSCs. Importantly, RAs may also constitute a means for HSCs to orchestrate the liver response to injury by triggering transcriptional effects in multiple additional surrounding liver cell populations. We envision that new approaches, such as single-cell technologies, will allow to better define how RAs are issued from LD loss in HSCs exert a multicellular control of the liver (patho)physiology.

Keywords: hepatic stellate cells; intercellular communications; lipid droplet; liver; liver injury; retinoids.

Figure 1

Potential role of RAs derived from the loss of RE-filled HSC LDs as an orchestrator of a multicellular response to liver injury. Schematic showing the basis for the proposal that RAs derived from the loss of RE-filled LD upon HSC activation may define a multicellular response to liver injury. Outstanding questions are indicated by question marks. See text for details. ECM, extracellular matrix; KC, Kupffer cells; LD, lipid droplet; LSEC, liver sinusoidal endothelial cells; Nuc., nucleus; RE, retinyl ester; RAs, retinoic acids.