Single-Nuclei RNA Sequencing Shows the Engagement of PPAR-Delta Target Genes Primarily in Hepatocytes and Cholangiocytes by the Selective PPAR-Delta Agonist Seladelpar

TL;DR

This study shows that the drug seladelpar activates specific genes mainly in liver cells called hepatocytes and cholangiocytes, which could help treat liver diseases.

Contribution

The study identifies the specific cell types in the liver where seladelpar activates PPARD target genes using single-nuclei RNA sequencing.

Findings

Seladelpar primarily activates PPARD target genes in hepatocytes and cholangiocytes.

Abcb4, a protective gene, is significantly upregulated in hepatocytes by seladelpar.

PPARD-responsive genes like Pdk4 and Angptl4 are increased in cholangiocytes and other nonparenchymal cells.

Abstract

The selective peroxisome proliferator–activated receptor delta (PPARD) agonist seladelpar reduces liver injury and modulates bile acid metabolism in preclinical models. Seladelpar was recently approved for the secondary treatment of primary biliary cholangitis (PBC). Despite its beneficial effects for liver diseases, the target cells of seladelpar on a single-cell level remain unknown. This study is aimed at investigating the effect of seladelpar on single liver cells.

CD-1 mice were gavaged with vehicle or seladelpar (10 mg/kg body weight), and the liver was harvested 6 h later. Single-nuclei RNA sequencing (snRNA-seq) analysis showed the engagement of PPARD target genes primarily in hepatocytes and cholangiocytes by seladelpar. The top two upregulated genes, Ehhadh and Cyp4a14, are related to fatty acid metabolism and were increased in hepatocytes, cholangiocytes, and Kupffer cells. Abcb4, an important canalicular transporter with hepatoprotective effects, was significantly upregulated in hepatocytes. We confirmed upregulated Abcb4 gene expression in seladelpar-treated primary mouse hepatocytes isolated from C57BL/6 mice. We further incubated nonparenchymal liver cells with seladelpar. Although there was a significant increase in the PPARD-responsive genes Pdk4 and Angptl4 in cholangiocytes, Kupffer cells, and hepatic stellate cells, seladelpar did not exert specific liver-protective effects in these cell types.

The selective PPARD agonist seladelpar induced PPARD-responsive genes primarily in hepatocytes and cholangiocytes. Seladelpar upregulated Abcb4 in hepatocytes, which might contribute to its beneficial effects in cholestatic liver disorders.

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