Liver X receptor

From Wikipedia, the free encyclopedia

nuclear receptor subfamily 1, group H, member 3
Identifiers
Symbol	NR1H3
HUGO	7966
Entrez	10062
OMIM	602423
RefSeq	NM_005693
UniProt	Q13133
Other data

nuclear receptor subfamily 1, group H, member 2
Identifiers
Symbol	NR1H2 UNR
HUGO	7965
Entrez	7376
OMIM	600380
RefSeq	NM_007121
UniProt	P55055
Other data

Contents 1 Introduction 2 Expression 3 Activation/ligands 4 Target Genes 5 Metabolism role of LXR 6 Clinical significance of LXR agonists 7 References 8 External links

[edit] Introduction

The liver X receptor (LXR), a member of the orphan receptor of the huge nuclear receptor family, is a transcription factor related to some other nuclear receptor PPAR, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis.

There are two isoforms known as LXRα and LXRβ. The liver X receptors are classified into the subfamily 1 (thyroid hormone receptor-like) of the nuclear receptor superfamily, and are given nuclear receptor nomenclature as NR1H3 (LXRα) and NR1H2 (LXRβ) respectively. LXRα and LXRβ were discovered seperately between 1994-1995 and later known as isoform to each other. LXRα isoform was identified by two groups and named RLD-1 ^[1] and LXR ^[2], whereas four groups identified the LXRβ isoform and named as UR ^[3], NER ^[4], OR-1 ^[5], and RIP-15 ^[6]. The human LXRα gene is located on chromosome 11p11.2, while the LXRβ gene is located on chromosome 19q13.3.

[edit] Expression

Although LXRα and LXRβ share high similarity in their DNA-binding domains and ligand-binding domains, expression of these two isoforms in various tissues differs a lot. LXRα expression is restricted to liver, kidney, intestine, fat tissue, macrophages, lung, and spleen and is highest in liver, hence the name liver X receptor α (LXRα). LXRβ is expressed in almost all tissues and organs, hence the early name UR (ubiquitous receptor). ^[7] The different pattern of expression suggests that LXRα and LXRβ has different role in regulating physiological function.

[edit] Activation/ligands

LXRα and LXRβ form heterodimers with the obligate partner 9-cis retinoic acid receptor (RXR). The LXR/RXR heterodimer can be activated with either an LXR agonist (oxysterols) or a RXR agonist (9-cis-retinoic acid). Oxysterols, the oxygenated derivatives of cholesterol, such as 22(R)-hydroxycholesterol,24(S)-hydroxycholesterol, 27-hydroxycholesterol, and cholestenoic acid, are the natural ligands for LXR. ^{[8][9][10][11]} After activation, LXR translocates to the nucleus and binds to LXR response element (LXRE), usually a variant of the idealized sequence AGGTCAN4AGGTCA, in the promoters of LXRs' target genes. Some synthetic LXR agonists have been developed, including nonsteroidal LXR agonists T0901317^[12] and GW3965.

[edit] Target Genes

Target genes of LXRs are involved in cholesterol and lipid metabolism regulation ^[13], including:

1. SREBP-1c (sterol response element-binding protein 1c) 2. FAS (fatty acid synthase) 3. CYP7A1 (cholesterol 7α-hydroxylase gene) 4. ApoE (apolipoprotein E) 5. CEPT (cholesterol ester transfer protein) 6. LXRα (liver X receptor α) 7. ABCA1 (ATP-binding cassette transporter A1) 8. ABCG1 (ATP-binding cassette transporter G1) 9. ABCG5 (ATP-binding cassette transporter G5) 10. ABCG8 (ATP-binding cassette transporter G8) 11. LPL (lipoprotein lipase)

[edit] Metabolism role of LXR

The importance of LXRs in physiological lipid and cholesterol metabolism suggests that they may influence the development of metabolic disorders such as hyper lipidemia and atherosclerosis. Evidence for this idea has been observed by recent studies that linked LXR activity to the pathogenesis of atherosclerosis. LXRα knockout mice are healthy when fed with a low-cholesterol diet. However, LXRα knockout mice develop enlarged fatty livers, degeneration of liver cells, high cholesterol levels in liver, and impaired liver function when fed a high-cholesterol diet^[14]. LXRβ knockout mice are unaffected by a high-cholesterol diet, suggesting that LXRα and LXRβ have separate roles. LXRs regulate fatty acid synthesis by modulating the expression of sterol regulatory elementbinding protein-1c (SREBP-1c).^[15][16] LXRs also regulate lipid homeostasis in the brain. LXRα and LXRβ double knockout mice develop neurodegenerative changes in brain tissue.^[17] LXRβ knockout mice results in adult-onset motor neuron degeneration in male mice. ^[18]

[edit] Clinical significance of LXR agonists

LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, anti-inflammation, and Alzheimer's disease. Treatment with LXR agonists (hypocholamide, T0901317, or GW3965) lowers the cholesterol level in serum and liver and inhibits the development of atherosclerosis in murine disease models.^[19][20][21] Synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance by regulating genes involved in glucose metabolism in liver and adipose tissue.^[22] GW3965 inhibits the expression of inflammatory mediators in cultured macrophage and inflammation in mice.^[23] LXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation of prostate cancer and breast cancer cells^[24] as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status^[25]. Treatment with T0901317 decreases amyloidal beta production in an Alzheimer's disease mouse model.^[26] However, both T0901317 and GW3965 have been reported to increase plasma and liver triglycerides in some mice models, indicating that T0901317 and GW3965 may not be a good candidate for a therapeutic agent. Developing new potent and effective LXR agonists without the undesirable side effects may be beneficial for clinical usage.

[edit] References

[edit] External links

• MeSH liver+X+receptor