A time- and space-resolved nuclear receptor atlas in mouse liver

Abstract

The unique functional versatility of the liver is paramount for organismal homeostasis. Both liver development and adult functions are controlled by tightly regulated transcription factor networks, within which nuclear receptors (NRs) regulate essential functions of parenchymal and non-parenchymal cells. Acting as transcription factors sensitive to extracellular cues such as steroidal hormones, lipid metabolites and xenobiotics and modulated by intracellular signaling pathways, NRs orchestrate many aspects of hepatic physiology. While liver functional zonation and adaptability to fluctuating conditions are known to rely on a sophisticated cellular architecture, a comprehensive knowledge of NRs functions in the different liver cell types is still lacking. As a first step toward the accurate mapping of NR functions in mouse liver, we characterized their levels of expression in whole liver as a function of time and diet, and explored NRs isoform expression in hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells and liver sinusoidal cells. In addition, we leveraged liver single cell RNAseq studies to provide here an up-to-date compendium of NR expression in mouse liver in space and time.

PPARβ/δ activation protects against hepatic ischaemia–reperfusion injury

“…Excessive inflammatory cytokines will activate the NF–κB signalling pathway, form a positive feedback inflammatory response, and ultimately aggravate the occurrence of apoptosis. Previous studies have found that PPARβ/δ is highly expressed not only in hepatocytes but also in KCs 31 . We found that activation of PPARβ/δ reduced the expression of inflammatory cytokines in KCs.…”

“…PPARβ/δ is highly expressed in hepatocytes and nonparenchymal cells, including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs) 31 . Our study indicated that PPARβ/δ affects the inflammatory response, and KCs are known to be the major effector cells of the inflammatory response in HIRI.…”

“…Previous studies have found that PPARβ/δ is highly expressed not only in hepatocytes but also in KCs. 31 We found that activation of PPARβ/δ reduced the expression of inflammatory cytokines in KCs. This will help to inhibit inflammation and apoptosis, ultimately alleviating HIRI.…”

FXR Friend-ChIPs in the Enterohepatic System

“…-catenin is a well-known and evolutionary conserved protein shown to be important in tightjunction formation, cell proliferation, and is integral to the Wnt signaling cascade (102). In the liver, -catenin regulates liver homeostasis, injury repair and tumorigenesis, and protein expression is mainly found in pericentral hepatocytes (103)(104)(105)(106). While a relationship has been identified, the molecular mechanism of -catenin and FXR interactions is undefined.…”

“…hepatocyte FXR function, and due to peri-central protein expression pattern of -catenin, exploration of interzonal and portal hepatocyte FXR should be further studied (103,106).…”