The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver

Abstract

Fibrosis contributes to ~45% of deaths in western countries. In chronic liver disease, fibrosis is a major factor determining outcomes, but efficient antifibrotic therapies are lacking. Although platelet-derived growth factor and transforming growth factor–β constitute key fibrogenic mediators, they do not account for the well-established link between cell death and fibrosis in the liver. Here, we hypothesized that damage-associated molecular patterns (DAMPs) may link epithelial cell death to fibrogenesis in the injured liver. DAMP receptor screening identified purinergic receptor P2Y14 among several candidates as highly enriched in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Conversely, P2Y14 ligands uridine 5′-diphosphate (UDP)–glucose and UDP-galactose were enriched in hepatocytes and were released upon different modes of cell death. Accordingly, ligand-receptor interaction analysis that combined proteomic and single-cell RNA sequencing data revealed P2Y14 ligands and P2Y14 receptor as a link between dying cells and HSCs, respectively. Treatment with P2Y14 ligands or coculture with dying hepatocytes promoted HSC activation in a P2Y14-dependent manner. P2Y14 ligands activated extracellular signal–regulated kinase (ERK) and Yes-associated protein (YAP) signaling in HSCs, resulting in ERK-dependent HSC activation. Global and HSC-selective P2Y14 deficiency attenuated liver fibrosis in multiple mouse models of liver injury. Functional expression of P2Y14 was confirmed in healthy and diseased human liver and human HSCs. In conclusion, P2Y14 ligands and their receptor constitute a profibrogenic DAMP pathway that directly links cell death to fibrogenesis.

The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome

“…Coherent with a potential increased usage of downstream-related metabolites such as UDP-Glc, depletion in early glycolytic intermediates (e.g., mannose-6-phosphate and glucose-6-phosphate) was observed in canonical UGT2B7 enzyme-expressing cells. Our findings further suggest that UGT enzymes may influence other cellular pathways in which UDP-sugars also participate, including the synthesis of the extracellular matrix component hyaluronan, protein glycosylation, and as ligands of the purinergic receptor P2Y14, which is involved in inflammation, asthma, fibrosis and acute kidney diseases [ 6 , 7 , 49 , 50 ].…”

“…UGTs also regulate the bioavailability and activity of diverse endogenous metabolites including the product of heme catabolism bilirubin, sex steroid hormones, signaling lipids and serotonin [ 1 , 3 , 4 , 5 ]. For example, a number of receptors are activated by substrates of UGT enzymes, including sex steroids and prostaglandins [ 3 , 6 , 7 ]. These metabolites are involved in signal transduction pathways that control key transcription factors acting as major regulators of gene expression programs [ 8 , 9 ].…”

Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease

“…Additionally, dying hepatocytes also release damage-associated molecular patterns, such as P2Y14 ligands and the alarmin IL33, which activate mouse and human hepatic stellate cells through direct and indirect mechanisms and thereby promote fibrogenesis. 112 , 113 …”

Understanding the cellular interactome of non-alcoholic fatty liver disease

“…19 Mederacke et al uncovered the purinergic receptor P2Y14 as highly enriched on HSCs and showed that the P2Y14 ligands UDP-glucose, UDP-galactose and UDP-glucuronic acid act as danger signals that are released upon liver injury and promote HSC activation and liver fibrosis. 48…”