# NR1H4

## Overview
The NR1H4 gene encodes the farnesoid X receptor (FXR), a nuclear receptor that plays a pivotal role in the regulation of bile acid, cholesterol, and glucose metabolism. As a member of the nuclear receptor subfamily 1 group H, FXR functions as a transcription factor, primarily expressed in the liver, intestine, kidney, and adrenal glands. It forms a heterodimer with the retinoid X receptor (RXR) to modulate the expression of target genes involved in metabolic processes (Hiebl2018Natural; Calkin2012Transcriptional). FXR is activated by bile acids and is integral to maintaining metabolic homeostasis, influencing pathways that regulate bile acid synthesis, glucose metabolism, and lipid homeostasis. The receptor's activity is modulated by various ligands, including natural bile acids and synthetic agonists, which bind to its ligand-binding domain (Li2021Structural; Downes2003A). Mutations in NR1H4 are linked to liver disorders such as progressive familial intrahepatic cholestasis type 5 and intrahepatic cholestasis of pregnancy, highlighting its clinical significance in hepatic and metabolic health (GomezOspina2016Mutations; Achermann2017Genetic).

## Structure
The NR1H4 gene encodes the farnesoid X receptor (FXR), a nuclear receptor involved in bile acid regulation. The primary structure of FXR consists of a sequence of amino acids forming the protein chain. The secondary structure includes alpha helices and beta sheets, typical of nuclear receptors, with the ligand-binding domain (LBD) characterized by a canonical fold comprising 10-13 alpha-helices and 2-5 beta-strands (Benoit2004Digging; Li2021Structural). The LBD forms a hydrophobic ligand-binding pocket, which is crucial for accommodating various ligands, including synthetic agonists like fexaramine and natural bile acids such as chenodeoxycholic acid (CDCA) (Downes2003A).

The tertiary structure of FXR involves the three-dimensional folding of the protein, which includes the LBD and a DNA-binding domain. The LBD's hydrophobic cavity is formed by 25 amino acid side chains, with a volume of 726 ų, allowing for specific interactions with ligands through van der Waals contacts and hydrogen bonding (Downes2003A). The quaternary structure may involve dimerization with other proteins, which is common among nuclear receptors (Li2021Structural).

FXR is subject to post-translational modifications, such as phosphorylation, which can influence its activity. Splice variants of NR1H4 may result in different isoforms with distinct functions, contributing to its diverse roles in metabolic regulation (Li2021Structural).

## Function
The NR1H4 gene encodes the farnesoid X receptor (FXR), a nuclear receptor that plays a critical role in regulating bile acid, cholesterol, and glucose metabolism. FXR is primarily expressed in the liver, intestine, kidney, and adrenal glands, where it functions as a transcription factor by forming a heterodimer with the retinoid X receptor (RXR) to modulate the expression of target genes (Hiebl2018Natural; Calkin2012Transcriptional).

FXR is activated by bile acids, such as chenodeoxycholic acid and cholic acid, and regulates bile acid synthesis, modification, absorption, and uptake through feedback and feedforward loops. It inhibits bile acid synthesis by inducing small heterodimer partner (SHP), which represses the expression of cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B1 (CYP8B1) (Calkin2012Transcriptional). FXR also influences the FGF15-JNK cascade in mice (or FGF19-JNK in humans) to further inhibit bile acid synthesis (Calkin2012Transcriptional).

In glucose metabolism, FXR reduces gluconeogenesis and enhances insulin sensitivity, contributing to glucose homeostasis. It also affects lipid metabolism by modulating lipoprotein composition and activating lipoprotein lipase activity, which is essential for maintaining cholesterol homeostasis and reducing cardiovascular disease risk (Calkin2012Transcriptional). FXR's regulatory functions are crucial for maintaining metabolic balance and protecting against liver disease (Calkin2012Transcriptional).

## Clinical Significance
Mutations in the NR1H4 gene, which encodes the farnesoid X receptor (FXR), are associated with several liver disorders, most notably progressive familial intrahepatic cholestasis type 5 (PFIC5). This rare autosomal recessive condition is characterized by severe cholestasis, low gamma-glutamyl transferase (GGT) levels, and rapid progression to liver failure, often necessitating liver transplantation (GomezOspina2016Mutations; Li2024NR1H4). Patients with PFIC5 typically present with early-onset liver dysfunction, including neonatal cholestasis and elevated serum alpha-fetoprotein (GomezOspina2016Mutations).

NR1H4 mutations also play a role in intrahepatic cholestasis of pregnancy (ICP), a condition marked by pruritus and liver dysfunction during pregnancy. Variants in NR1H4 have been linked to reduced receptor activity, contributing to the development of ICP (Achermann2017Genetic).

Alterations in NR1H4 expression are implicated in inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Certain single nucleotide polymorphisms (SNPs) in NR1H4 may confer protection or increase susceptibility to IBD by affecting FXR function, which is crucial for maintaining intestinal barrier integrity and regulating immune responses (Koutsounas2015Farnesoid; Attinkara2012Association).

## Interactions
NR1H4, also known as FXR, is a nuclear receptor that plays a significant role in regulating autophagy and ciliogenesis through its interactions with various proteins. It is known to bind to promoter regions and suppress the transcription of autophagy genes, thereby repressing autophagy and negatively impacting cilia formation (Liu2018Ciliogenesis). NR1H4 interacts with PPARA, where it can repress PPARA-induced ciliogenesis by regulating autophagy. This interaction is evidenced by increased levels of autophagic markers and gene expression when NR1H4 is knocked down, which are further enhanced by PPARA activation (Liu2018Ciliogenesis).

In the context of kidney function, NR1H4 activation through its ligand GW 4064 inhibits cilia formation and exacerbates kidney damage by blocking autophagy. This is demonstrated by the prevention of starvation-induced reduction of proteins like SQSTM1 and OFD1, which are involved in ciliogenesis (Liu2018Ciliogenesis). NR1H4 is also involved in a network of nuclear receptors, potentially regulating the promoter of SHP [NR0B2] and participating in feedback loops, although specific interactions with SHP are not detailed (Amoutzias2007A). These interactions highlight NR1H4's role in complex regulatory pathways affecting cellular processes.


## References


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[12. (Li2024NR1H4) Zhong-Die Li, Yu-Chuan Li, Jing-Zhao, Jian-She Wang, and Xin-Bao Xie. Nr1h4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death. Orphanet Journal of Rare Diseases, April 2024. URL: http://dx.doi.org/10.1186/s13023-024-03166-1, doi:10.1186/s13023-024-03166-1. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13023-024-03166-1)