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

Abstract

The functional versatility of the liver is paramount for organismal homeostasis. Adult liver functions are controlled by a tightly regulated transcription factor network including nuclear receptors (NRs), which orchestrate many aspects of hepatic physiology. NRs are transcription factors sensitive to extracellular cues such as hormones, lipids, xenobiotics etc. and are modulated by intracellular signaling pathways. While liver functional zonation and adaptability to fluctuating conditions rely on a sophisticated cellular architecture, a comprehensive knowledge of NR functions within liver cell populations is still lacking. As a step toward the accurate mapping of NR functions in liver, we characterized their levels of expression in whole liver from C57Bl6/J male mice as a function of time and diet. Nr1d1 (Rev-erbα), Nr1d2 (Rev-erbβ), Nr1c2 (Pparβ/δ) and Nr1f3 (Rorγ) exhibited a robust cyclical expression in ad libitum-fed mice which was, like most cyclically expressed NRs, reinforced upon time-restricted feeding. In a few instances, cyclical expression was lost or gained as a function of the feeding regimen. NR isoform expression was explored in purified hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells and liver sinusoidal cells. The expression of some NR isoforms, such as Nr1h4 (Fxrα) and Nr1b1 (Rarα) isoforms, was markedly restricted to a few cell types. Leveraging liver single cell RNAseq studies yielded a zonation pattern of NRs in hepatocytes, liver sinusoidal cells and stellate cells, establishing a link between NR subtissular localization and liver functional specialization. In summary, we 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

“…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

“…102 In the liver, β-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 β-catenin and FXR interactions is undefined. In mouse models of hepatocellular carcinoma (HCC), FXR and β-catenin expression patterns display an inverse relationship.…”

“…Taken together, these studies indicate that the FXR/ β-catenin complex inhibits hepatocyte FXR function, and due to peri-central protein expression pattern of β-catenin, exploration of interzonal and portal hepatocyte FXR should be further studied. 103,106 However, the formation of this complex may be transient, depending on injury caused by experimental cholestasis model, hepatocyte zonation, or ligand activation.…”

Bile Acids Serve As Endogenous Antagonists Of The Leukemia Inhibitory Factor (LIF) Receptor in Oncogenesis

“…12,16 However, the epithelial-damaging effects, underlying these pro-oncogenic properties, manifest at concentrations of bile acids > 100 µM while, at physiological intracellular concentrations (that are in the nano-micromolamolar range), bile acids are not cytotoxic and function as signalling molecules activating a family of cell membrane and nuclear receptors, known as bile acid-activated receptors, that maintains tissue and immune homeostasis. The Farnesoid-X-receptor (FXR), a receptor for primary bile acids 18 , and the G protein-coupled bile acid receptor 1 (GPBAR1) 20 , a receptor for secondary bile acids, are the two main bile acid sensors, functioning as integrative hubs between the intestinal microbiota and host metabolism and immunity 22 . Of relevance, FXR and GPBAR1 activation by natural and synthetic agonists 24,26 confers protection against colorectal cancers development, while their genetic ablation promotes entero-hepatic tumorigenesis in animal models 28,30,31 .…”