Pathway Human Homo sapiens

NR1H2 and NR1H3-mediated signaling

R-HSA-9024446 in Reactome release 97: under Signaling by Nuclear Receptors, with 47 genes placed in it by the mapping files and 6 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9024446 (mouse), R-RNO-9024446 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

Scripts are off

This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9024446.3
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2019-09-10
Events inside: 6, counted from the record
Also named: LXR-mediated signaling

The liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are members of the nuclear receptor superfamily and function as ligand-activated transcription factors. The natural ligands of NR1H2 and NR1H3 are oxysterols (e.g., 24(S),25-epoxycholesterol, 24(S)-hydroxycholesterol (OH), 25-OH, and 27-OH) that are produced endogenously by enzymatic reactions, by reactive oxygen species (ROS)-dependent oxidation of cholesterol and by the alimentary processes (reviewed in:Jakobsson T et al. 2012; Huang C 2014; Komati R et al. 2017). It has been shown that these oxysterols bind directly to the ligand-binding domain of LXRs with Kd values ranging from 0.1 to 0.4 microM. 24(S), 25-epoxycholesterol was found to be the most potent endogenous agonist (Janowski BA et al. 1999). NR1H3 (LXRα) and NR1H2 (LXRβ) showed similar affinities for these compounds (Janowski BA et al. 1999). In physiological conditions, oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore the LXRs operate as cholesterol sensors to alter gene expression and protect the cells from cholesterol overload via: (1) inhibiting intestinal cholesterol absorption; (2) stimulating cholesterol efflux from cells to high-density lipoproteins through the ATP-binding cassette transporters ABCA1 and ABCG1: (3) activating the conversion of cholesterol to bile acids in the liver; and (4) activating biliary cholesterol and bile acid excretion (reviewed in: Wójcicka G et al. 2007; Baranowski M 2008; Laurencikiene J & Rydén M 2012; Edwards PA et al. 2002; Zelcer N & Tontonoz P 2006; Zhao C & Dahlman-Wright K 2010). In addition, LXR agonists enhance de novo fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and hepatic steatosis (Wójcicka G et al. 2007; Baranowski M 2008; Laurencikiene J & Rydén M 2012). In addition to their function in lipid metabolism, NR1H2,3 have also been found to modulate immune and inflammatory responses in macrophages (Zelcer N & Tontonoz P 2006). The NR1H2 and NR1H3 molecules can be viewed as having four functional domains: (1) an amino-terminal ligand-independent activation function domain (AF-1), which may stimulate transcription in the absence of ligand; (2) a DNA-binding domain (DBD) containing two zinc fingers; (3) a hydrophobic ligand-binding domain (LBD) required for ligand binding and receptor dimerization; and, (4) a carboxy-terminal ligand-dependent transactivation sequence (also referred to as the activation function-2 (AF-2) domain) that stimulates transcription in response to ligand binding (Robinson-Rechavi M et al. 2003; Jakobsson T et al. 2012; Färnegardh M et al. 2003; Lin CY & Gustafsson JA 2015). Although both NR1H3 and NR1H2 are activated by the same ligands and are structurally similar, their tissue expression profiles are very different. NR1H3 is selectively expressed in specific tissues and cell types, such as the liver, intestine, adrenal gland, adipose tissue and macrophages, whereas NR1H2 is ubiquitously expressed (Nishimura M et al. 2004; Bookout AL et al. 2006). Upon activation NR1H2 or NR1H3 heterodimerizes with retinoid X receptors (RXR) and binds to LXR-response elements (LXREs) consisting of a direct repeat of the core sequence 5'-AGGTCA-3' separated by 4 nucleotides (DR4) in the DNA of target genes (Wiebel FF & Gustafsson JA 1997). An inverted repeat of the same consensus sequence with no spacer region(IR-0) and an inverted repeat of the same consensus sequence separated by a 1 bp spacer (IR-1) have also been shown to mediate LXR transactivation (Mak PA et al. 2002, Landrier JF et al. 2003). NR1H3 and NR1H2 have been shown to regulate gene expression via LXREs in the promoter regions of their target genes such as UDP glucuronosyltransferase 1 family, polypeptide A3 (UGT1A3) (Verreault M et al. 2006), fatty acid synthase (FAS) (Joseph SB et al. 2002a), carbohydrate response element binding protein (ChREBP, also known as MLX-interacting protein-like or MLXIPL) (Cha JY & Repa JJ 2007) and phospholipid transfer protein (PLTP) (Mak PA et al. 2002). LXREs have also been reported to be present in introns of target genes such as the ATP-binding cassette transporter G1 (ABCG1) (Sabol SL et al. 2005). NR1H3 has been shown to activate gene expression via the FXR-responsive element found in the proximal promoter of the human ileal bile acid-binding protein (FABP6) (Landrier JF et al. 2003). The NR1H2,3:RXR heterodimers are permissive, in that they can be activated by ligands for either NR1H2,3 (LXR) or RXR (Willy PJ et al. 1995).

Literature Reactome attaches

Liver X receptor biology and pharmacology: new pathways, challenges and opportunitiesTrends Pharmacol. Sci., 2012, vol. 33, p. 394-404PubMed 22541735
Liver X receptors (LXRs). Part I: structure, function, regulation of activity, and role in lipid metabolismPostepy Hig Med Dosw (Online), 2007, vol. 61, p. 736-59PubMed 18063918

Reactome's record lists 8 orthologous events, R-RNO-9024446 (Rattus norvegicus), R-MMU-9024446 (Mus musculus) among the species this site serves, and 6 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"NR1H2 and NR1H3-mediated signaling". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9024446 with StableID: R-HSA-9024446.3 (accessed 2026-10-01 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 47 genes in this human pathway; showing 1 to 47, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneABCA1	AuthorityHGNC:29	Mapping file id19 NCBI file	EvidenceTAS
GeneABCG1	AuthorityHGNC:73	Mapping file id9619 NCBI file	EvidenceTAS
GeneABCG5	AuthorityHGNC:13886	Mapping file id64240 NCBI file	EvidenceTAS
GeneABCG8	AuthorityHGNC:13887	Mapping file id64241 NCBI file	EvidenceTAS
GeneAGO1	AuthorityHGNC:3262	Mapping file id26523 NCBI file	EvidenceTAS
GeneAGO2	AuthorityHGNC:3263	Mapping file id27161 NCBI file	EvidenceTAS
GeneAGO3	AuthorityHGNC:18421	Mapping file id192669 NCBI file	EvidenceTAS
GeneAGO4	AuthorityHGNC:18424	Mapping file id192670 NCBI file	EvidenceTAS
GeneANGPTL3	AuthorityHGNC:491	Mapping file id27329 NCBI file	EvidenceTAS
GeneAPOC1	AuthorityHGNC:607	Mapping file id341 NCBI file	EvidenceTAS
GeneAPOC2	AuthorityHGNC:609	Mapping file id344 NCBI file	EvidenceTAS
GeneAPOC4	AuthorityHGNC:611	Mapping file id346 NCBI file	EvidenceTAS
GeneAPOD	AuthorityHGNC:612	Mapping file id347 NCBI file	EvidenceTAS
GeneAPOE	AuthorityHGNC:613	Mapping file id348 NCBI file	EvidenceTAS
GeneARL4C	AuthorityHGNC:698	Mapping file id10123 NCBI file	EvidenceTAS
GeneCETP	AuthorityHGNC:1869	Mapping file id1071 NCBI file	EvidenceTAS
GeneEEPD1	AuthorityHGNC:22223	Mapping file id80820 NCBI file	EvidenceTAS
GeneEP300	AuthorityHGNC:3373	Mapping file id2033 NCBI file	EvidenceTAS
GeneFABP6	AuthorityHGNC:3561	Mapping file id2172 NCBI file	EvidenceTAS
GeneFASN	AuthorityHGNC:3594	Mapping file id2194 NCBI file	EvidenceTAS
GeneGPS2	AuthorityHGNC:4550	Mapping file id2874 NCBI file	EvidenceTAS
GeneHDAC3	AuthorityHGNC:4854	Mapping file id8841 NCBI file	EvidenceTAS
GeneKDM1A	AuthorityHGNC:29079	Mapping file id23028 NCBI file	EvidenceTAS
GeneKDM1B	AuthorityHGNC:21577	Mapping file id221656 NCBI file	EvidenceTAS
GeneKDM3A	AuthorityHGNC:20815	Mapping file id55818 NCBI file	EvidenceTAS
GeneKDM4A	AuthorityHGNC:22978	Mapping file id9682 NCBI file	EvidenceTAS
GeneMOV10	AuthorityHGNC:7200	Mapping file id4343 NCBI file	EvidenceTAS
GeneMYLIP	AuthorityHGNC:21155	Mapping file id29116 NCBI file	EvidenceTAS
GeneNCOA1	AuthorityHGNC:7668	Mapping file id8648 NCBI file	EvidenceTAS
GeneNCOR1	AuthorityHGNC:7672	Mapping file id9611 NCBI file	EvidenceTAS
GeneNCOR2	AuthorityHGNC:7673	Mapping file id9612 NCBI file	EvidenceTAS
GeneNR1H2	AuthorityHGNC:7965	Mapping file id7376 NCBI file	EvidenceTAS
GeneNR1H3	AuthorityHGNC:7966	Mapping file id10062 NCBI file	EvidenceTAS
GeneNRIP1	AuthorityHGNC:8001	Mapping file id8204 NCBI file	EvidenceTAS
GenePCK1	AuthorityHGNC:8724	Mapping file id5105 NCBI file	EvidenceTAS
GenePLIN1	AuthorityHGNC:9076	Mapping file id5346 NCBI file	EvidenceTAS
GenePLTP	AuthorityHGNC:9093	Mapping file id5360 NCBI file	EvidenceTAS
GeneRXRA	AuthorityHGNC:10477	Mapping file id6256 NCBI file	EvidenceTAS
GeneRXRB	AuthorityHGNC:10478	Mapping file id6257 NCBI file	EvidenceTAS
GeneSCD	AuthorityHGNC:10571	Mapping file id6319 NCBI file	EvidenceTAS
GeneSREBF1	AuthorityHGNC:11289	Mapping file id6720 NCBI file	EvidenceTAS
GeneTBL1X	AuthorityHGNC:11585	Mapping file id6907 NCBI file	EvidenceTAS
GeneTBL1XR1	AuthorityHGNC:29529	Mapping file id79718 NCBI file	EvidenceTAS
GeneTNRC6A	AuthorityHGNC:11969	Mapping file id27327 NCBI file	EvidenceTAS
GeneTNRC6B	AuthorityHGNC:29190	Mapping file id23112 NCBI file	EvidenceTAS
GeneTNRC6C	AuthorityHGNC:29318	Mapping file id57690 NCBI file	EvidenceTAS
GeneUGT1A3	AuthorityHGNC:12535	Mapping file id54659 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Signaling by Nuclear ReceptorsR-HSA-9006931296 genes

Children

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.