NR1H3
Description
The NR1H3 (nuclear receptor subfamily 1 group H member 3) is a protein-coding gene located on chromosome 11.
NR1H3, also known as Liver X receptor alpha (LXR-alpha), is a nuclear receptor protein. It is a key regulator of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. NR1H3 is highly expressed in liver, adrenal gland, intestine, adipose tissue, macrophages, lung, and kidney. It forms heterodimers with retinoid X receptors (RXRs) and regulates expression of target genes containing LXR response elements. Restoration of NR1H3 expression/function within a psoriatic lesion may help to switch the transition from psoriatic to symptomless skin. NR1H3 interacts with EDF1 and small heterodimer partner. It activates the transcription factor SREBP-1c, resulting in lipogenesis. NR1H3 is autoregulated by miRNA hsa-miR-613, which targets the endogenous LXRα through its specific miRNA response element within the LXRα 3′-untranslated region. NR1H3 autoregulates its own suppression via induction of SREBP1c which upregulates miRNA has-miR-613.
NR1H3 is a nuclear receptor that exhibits ligand-dependent transcriptional activation activity. It interacts with retinoic acid receptor (RXR) to activate retinoid responses through target genes defined by LXRES, which are DR4-type response elements. NR1H3 plays a critical role in cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8. It also interacts functionally with RORA for the regulation of genes involved in liver metabolism. NR1H3 induces LPCAT3-dependent phospholipid remodeling in endoplasmic reticulum (ER) membranes of hepatocytes, driving SREBF1 processing and lipogenesis. Through LPCAT3, NR1H3 triggers the incorporation of arachidonate into phosphatidylcholines of ER membranes, increasing membrane dynamics and enabling triacylglycerols transfer to nascent very low-density lipoprotein (VLDL) particles. NR1H3 also counteracts lipid-induced ER stress response and inflammation, likely by modulating SRC kinase membrane compartmentalization and limiting the synthesis of lipid inflammatory mediators.
NR1H3 is also known as LXR-a, LXRA, RLD-1.
