Liver X receptor
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| LXRα (nuclear receptor subfamily 1, group H, member 3)
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| Identifiers | |
| Symbol | NR1H3 |
| Entrez | 10062 |
| HUGO | 7966 |
| OMIM | 602423 |
| RefSeq | NM_005693 |
| UniProt | Q13133 |
| Other data | |
| LXRβ (nuclear receptor subfamily 1, group H, member 2)
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| Identifiers | |
| Symbol | NR1H2 |
| Alt. Symbols | UNR |
| Entrez | 7376 |
| HUGO | 7965 |
| OMIM | 600380 |
| RefSeq | NM_007121 |
| UniProt | P55055 |
| Other data | |
The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as PPAR, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. Since there is no clear consensus on what the endogenous ligand of LXR is, LXR is referred to as an orphan receptor.
Two isoforms of LXR have been identified and are referred to as LXRα and LXRβ. The liver X receptors are classified into subfamily 1 (thyroid hormone receptor-like) of the nuclear receptor superfamily, and are given the nuclear receptor nomenclature symbols NR1H3 (LXRα) and NR1H2 (LXRβ) respectively.
LXRα and LXRβ were discovered separately between 1994-1995. LXRα isoform was independently identified by two groups and initially named RLD-1[1] and LXR,[1] whereas four groups identified the LXRβ isoform and called it UR,[1] NER,[1] OR-1,[1] and RIP-15.[1] The human LXRα gene is located on chromosome 11p11.2, while the LXRβ gene is located on chromosome 19q13.3.
Contents |
Expression
While the expression of LXRα and LXRβ in various tissues somewhat overlap, the tissue distribution pattern of these two isoforms overall differ considerably. 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).[1] The different pattern of expression suggests that LXRα and LXRβ have different roles in regulating physiological function.
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.[1][1][1][1] 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[1] and GW3965.
Target Genes
Target genes of LXRs are involved in cholesterol and lipid metabolism regulation,[1] including:
- ABC - ATP Binding Cassette transporter isoforms A1, G1, G5, and G8
- ApoE - Apolipoprotein E
- CETP - CholEsterylester Transfer Protein
- CYP7A1 - CYtochrome P450 isoform 7A1 - cholesterol 7α-hydroxylase
- FAS - Fatty Acid Synthase
- LPL - LipoProtein Lipase
- LXR-α - Liver X Receptor-α (a somewhat unusual example of receptor up-regulating its own expression)
- SREBP-1c - Sterol Regulatory Element Binding Protein 1c
Roles of LXR in metabolism
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.[1] 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).[1][1] LXRs also regulate lipid homeostasis in the brain. LXRα and LXRβ double knockout mice develop neurodegenerative changes in brain tissue.[1] LXRβ knockout mice results in adult-onset motor neuron degeneration in male mice.[1]
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.[1][1][1] 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.[1] GW3965 inhibits the expression of inflammatory mediators in cultured macrophage and inflammation in mice.[1] LXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation of prostate cancer and breast cancer cells[1] as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status[1]. Treatment with T0901317 decreases amyloidal beta production in an Alzheimer's disease mouse model.[1] 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.
References
External links
Transcription factors and intracellular receptors | |||||||||||||
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| (1) Basic domains |
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| (2) Zinc finger DNA-binding domains |
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| (3) Helix-turn-helix domains |
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| (4) β-Scaffold factors with minor groove contacts |
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| (0) Other transcription factors |
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Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
