Nuclear receptors form the largest family of transcription factors, with forty-eight members in humans and forty-nine in rodents. By binding a variety of lipophilic ligands — steroid hormones, fat-soluble vitamins, bile and fatty acids — they regulate the expression of numerous genes involved in metabolism, reproduction and development. In the liver, they govern essential functions such as glucose metabolism, cholesterol and bile acid homeostasis, and contribute to hepatoprotective mechanisms, notably against bile acid toxicity. As such, they represent leading pharmacological targets in metabolic and cholestatic liver diseases. However, since hepatocytes account for approximately 70% of liver cells under normal conditions, analyzing nuclear receptors at the whole-liver scale mainly reflects their hepatocyte profile and may mask their expression in non-parenchymal cells.
To clarify this distribution, the researchers isolated five cell types — hepatocytes, cholangiocytes, hepatic stellate cells, sinusoidal endothelial cells and Kupffer cells — from the livers of mice with acute cholestasis (induced by bile duct ligation) or chronic cholestasis (Abcb4−/− mice), compared with healthy controls. The expression of 43 of the 49 receptors was detected by RT-qPCR in one or more cell types, including four exclusively in non-parenchymal cells. Under normal conditions, the receptors were expressed at higher levels within the isolated cell types than in the whole liver, and half of them reached their maximal expression in non-parenchymal cells.
The cholestasis-associated alterations differed depending on the model. After bile duct ligation, the messenger RNA changes predominantly involved non-parenchymal cells and consisted mainly of downregulations, with the most pronounced changes affecting stellate cells — an observation that the authors link to the role of these receptors in the transdifferentiation of stellate cells into myofibroblasts, and therefore in fibrosis progression. In Abcb4−/− mice, the variations were as frequent in hepatocytes as in non-parenchymal cells: downregulations predominated in hepatocytes, stellate cells and cholangiocytes, contrasting with upregulations in sinusoidal endothelial and Kupffer cells. Undetectable in the whole liver, the vitamin D receptor (Vdr) was upregulated in all non-parenchymal cells of Abcb4−/− mice, reinforcing the interest in this target in chronic cholestatic diseases.
In conclusion, non-parenchymal cells constitute a major site of nuclear receptor expression, which is markedly remodeled during cholestasis, mainly through downregulation, reflecting substantial changes in metabolic activity. These cells thus emerge as novel targets to consider in therapies directed against nuclear receptors.