Liver X receptor

Last updated
LXRα (nuclear receptor subfamily 1, group H, member 3)
LXRa-RXR whole structure.png
LXRα-RXRβ heterodimeric structure (PDB 1UHL).
Identifiers
SymbolNR1H3
NCBI gene 10062
HGNC 7966
OMIM 602423
RefSeq NM_005693
UniProt Q13133
Search for
Structures Swiss-model
Domains InterPro
LXRβ (nuclear receptor subfamily 1, group H, member 2)
Identifiers
SymbolNR1H2
Alt. symbolsUNR
NCBI gene 7376
HGNC 7965
OMIM 600380
RefSeq NM_007121
UniProt P55055
Search for
Structures Swiss-model
Domains InterPro

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 the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

Contents

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, [2] whereas four groups identified the LXRβ isoform and called it 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.

Expression

While the expression of LXRα and LXRβ in various tissues overlap the tissue distribution pattern of these two isoforms 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). [7] The different pattern of expression suggests that LXRα and LXRβ have different roles in regulating physiological function.

Structure

Crystal structure of human liver X receptor β (LXRβ) forms a heterodimer with its partner retinoid X receptor α (RXRα) on its cognate element an AGGTCA direct repeat spaced by 4 nucleotides showing an extended X-shaped arrangement with DNA- and ligand-binding domains crossed. In contrast, the parallel domain arrangement of other NRs bind an AGGTCA direct repeat spaced by 1 nucleotide. The LXRβ core binds DNA via canonical contacts and auxiliary DNA contacts that enhance affinity for the response element. [8]

LXRa-RXRb active site with T-0901317 bound (PDB 1UHL). LXR-RXR bound polar contacts.png
LXRα-RXRβ active site with T-0901317 bound (PDB 1UHL).

Crystal structure of human liver X receptor α (LXRα) also forms a heterodimer with its partner retinoid X receptor β (RXRβ). The LXRα-RXRβ heterodimer (PDB 1UHL) binds synthetic LXR oxysterol agonist T-0901317. The ligand-binding pocket predominantly consists of hydrophobic residues. The most critical residues to the binding pocket include E267, R305, H421, and W443. The binding pocket accommodates oxysterols of molecular volumes up to 400 Å3 and T-0901317 easily positions itself with a molecular volume of 304 Å3. H421 forms a hydrogen bond with T-0901317's hydroxyl head group which lowers the pKa of the H421 imidazole side chain. As a result, the imidazole side chain interacts electrostatically with π-electrons of W443's indole side chain to stabilize the active conformation of the helices. [9]

The phenyl group of T-0901317 extends toward the β-sheet side of the binding pocket and partially occupies it. The unoccupied section contains hydrophilic, polar residues E267 and R305. H421 and W443 anchor the 22-, 24-, or 27-hydroxyl group of an oxysterol to the binding pocket via hydrogen bonding and electrostatic interactions. The conformational flexibility of R305 allows it to bind the 3-hydroxyl group and stabilize an oxysterol. [9]

Activation/ligands

LXRα and LXRβ form heterodimers with the obligate partner retinoid X receptor (RXR), which is activated by 9-cis-13,14-dihydroretinoic acid. [10] The LXR/RXR heterodimer can be activated with either an LXR agonist (oxysterols) or a RXR agonist (9-cis-13,14-dihydroretinoic 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. [11] [12] [13] [14] After activation, LXR 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 [15] and GW3965.

The hexacyclic aromatic ketones, (-)anthrabenzoxocinone and (-)bischloroanthrabenzoxocinone ((-)-BABX) derived from a Streptomyces sp. have micromolar affinity for LXR-α. [16]

LXR-623 (WAY 252623) CAS: [875787-07-8].

Target genes

LXR-RXR nuclear receptor heterodimers function as transcriptional regulators for genes involved in lipid metabolism, lipid homeostasis, and inflammation. [9] Target genes of LXRs are involved in cholesterol and lipid metabolism regulation, [17] including:

Role in metabolism

The importance of LXRs in physiological lipid and cholesterol metabolism suggests that they may influence the development of metabolic disorders such as hyperlipidemia 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. [18] 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 element binding protein-1c (SREBP-1c). [19] [20] LXRs also regulate lipid homeostasis in the brain. LXRα and LXRβ double knockout mice develop neurodegenerative changes in brain tissue. [21] LXRβ knockout mice results in adult-onset motor neuron degeneration in male mice. [22]

Adiponectin induces ABCA1-mediated reverse cholesterol transport by activation of PPAR-γ and LXRα/β. [23]

Potential therapeutic applications of LXR agonists

LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, anti-inflammation, Alzheimer's disease, and cancer.

Cardiovascular

Treatment with LXR agonists (hypocholamide, T0901317, GW3965, or N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA)) lowers the cholesterol level in serum and liver and inhibits the development of atherosclerosis in murine disease models. [24] [25] [26] [27] 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. [28] GW3965 inhibits the expression of inflammatory mediators in cultured macrophage and inflammation in mice. [29]

Aberrant LXR signaling in macrophages due to the oxidized cholesterol 7-ketocholesterol promotes the inflammation that leads to atherosclerosis. [30] For this reason, 7-ketocholesterol is a therapeutic target for the prevention and treatment of atherosclerosis. [30]

When lipogenesis is increased by pharmacological activation of the liver X receptor, hepatic VLDL production is increased 2.5-fold, and the liver produces large TG-rich VLDL particles. Glucose induces expression of LXR target genes involved in cholesterol homeostasis like ABCA1 which is defective in Tangier disease. A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. LXR heterodimerises with RXR. Promiscuous RXR also heterodimerises with PPAR members. PPAR-α plays a pivotal role in fatty acid catabolism in liver by upregulating the expression of numerous genes involved in mitochondrial fatty acid oxidation. Thus RXR is a common partner of two nuclear receptors acting in opposite directions with regard to fatty acid metabolism. So both LXR and PPAR-α compete for the limited pool of RXR and this dynamic equilibrium determines the direction of lipid metabolism. [31]

Developing new potent and effective LXR agonists without the undesirable side effects may be beneficial for clinical usage. [32] In this regard, DMHCA was reported to reduce atherosclerosis in apolipoprotein E-deficient mice without inducing hypertriglyceridemia and liver steatosis. [27]

Alzheimer's disease

Treatment with T0901317 decreases amyloidal beta production in an Alzheimer's disease mouse model. [33] 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.

Cancer

LXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation of prostate cancer and breast cancer cells [34] as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status. [35]

Related Research Articles

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor</span> Group of nuclear receptor proteins

In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.

<span class="mw-page-title-main">Sterol regulatory element-binding protein</span> Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for RARA, five for RARB, and two for RARG. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. RAR receptors are also known to exhibit many retinoid-independent effects as they bind to and regulate other nuclear receptor pathways, such as the estrogen receptor.

The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which may be an endogenous mammalian RXR-selective agonist. Bexarotene is the only specific activator of the RXRs which does not activate the Retinoic Acid Receptors.

<span class="mw-page-title-main">Farnesoid X receptor</span> Protein-coding gene in the species Homo sapiens

The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4, is a nuclear receptor that is encoded by the NR1H4 gene in humans.

<span class="mw-page-title-main">Constitutive androstane receptor</span> Protein-coding gene in humans

The constitutive androstane receptor (CAR) also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene. CAR is a member of the nuclear receptor superfamily and along with pregnane X receptor (PXR) functions as a sensor of endobiotic and xenobiotic substances. In response, expression of proteins responsible for the metabolism and excretion of these substances is upregulated. Hence, CAR and PXR play a major role in the detoxification of foreign substances such as drugs.

<span class="mw-page-title-main">Nuclear receptor</span> Protein

In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.

The RAR-related orphan receptors (RORs) are members of the nuclear receptor family of intracellular transcription factors. There are three forms of ROR, ROR-α, -β, and -γ and each is encoded by a separate gene, RORA, RORB, and RORC respectively. The RORs are somewhat unusual in that they appear to bind as monomers to hormone response elements as opposed to the majority of other nuclear receptors which bind as dimers. They bind to DNA elements called ROR response elements (RORE).

<span class="mw-page-title-main">Small heterodimer partner</span> Protein found in humans

The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.

<span class="mw-page-title-main">Retinoid X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor alpha</span> Nuclear receptor protein found in humans

Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1, is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the PPARA gene. Together with peroxisome proliferator-activated receptor delta and peroxisome proliferator-activated receptor gamma, PPAR-alpha is part of the subfamily of peroxisome proliferator-activated receptors. It was the first member of the PPAR family to be cloned in 1990 by Stephen Green and has been identified as the nuclear receptor for a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.

<span class="mw-page-title-main">Liver X receptor alpha</span> Nuclear receptor protein found in humans

Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.

<span class="mw-page-title-main">Retinoid X receptor beta</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor delta</span> Nuclear receptor protein found in humans

Peroxisome proliferator-activated receptor delta(PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1(NUC1) is a nuclear receptor that in humans is encoded by the PPARD gene.

<span class="mw-page-title-main">Retinoic acid receptor gamma</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor gamma (RAR-γ), also known as NR1B3 is a nuclear receptor encoded by the RARG gene. Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma and its agonism of the gamma subtype is largely responsible for adapalene's observed effects.

<span class="mw-page-title-main">Liver X receptor beta</span> Protein-coding gene in the species Homo sapiens

Liver X receptor beta (LXR-β) is a member of the nuclear receptor family of transcription factors. LXR-β is encoded by the NR1H2 gene.

<span class="mw-page-title-main">INSIG2</span> Protein-coding gene in the species Homo sapiens

Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.

24<i>S</i>-Hydroxycholesterol Chemical compound

24S-Hydroxycholesterol (24S-HC), also known as cholest-5-ene-3,24-diol or cerebrosterol, is an endogenous oxysterol produced by neurons in the brain to maintain cholesterol homeostasis. It was discovered in 1953 by Alberto Ercoli, S. Di Frisco, and Pietro de Ruggieri, who first isolated the molecule in the horse brain and then demonstrated its presence in the human brain.

<span class="mw-page-title-main">Peter Tontonoz</span>

Peter Tontonoz is a physician-scientist and academic. He is the Frances and Albert Piansky Endowed Chair and Distinguished Professor of Pathology and Laboratory Medicine and of Biological Chemistry at the University of California, Los Angeles.

References

  1. ↑ Apfel R, Benbrook D, Lernhardt E, Ortiz MA, Salbert G, Pfahl M (October 1994). "A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily". Mol. Cell. Biol. 14 (10): 7025–35. doi:10.1128/mcb.14.10.7025. PMC   359232 . PMID   7935418.
  2. ↑ Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ (May 1995). "LXR, a nuclear receptor that defines a distinct retinoid response pathway". Genes Dev. 9 (9): 1033–45. doi: 10.1101/gad.9.9.1033 . PMID   7744246.
  3. ↑ Song C, Kokontis JM, Hiipakka RA, Liao S (November 1994). "Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors". Proc. Natl. Acad. Sci. U.S.A. 91 (23): 10809–13. Bibcode:1994PNAS...9110809S. doi: 10.1073/pnas.91.23.10809 . PMC   45115 . PMID   7971966.
  4. ↑ Shinar DM, Endo N, Rutledge SJ, Vogel R, Rodan GA, Schmidt A (September 1994). "NER, a new member of the gene family encoding the human steroid hormone nuclear receptor". Gene. 147 (2): 273–6. doi:10.1016/0378-1119(94)90080-9. PMID   7926814.
  5. ↑ Teboul M, Enmark E, Li Q, Wikström AC, Pelto-Huikko M, Gustafsson JA (March 1995). "OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor". Proc. Natl. Acad. Sci. U.S.A. 92 (6): 2096–100. Bibcode:1995PNAS...92.2096T. doi: 10.1073/pnas.92.6.2096 . PMC   42430 . PMID   7892230.
  6. ↑ Seol W, Choi HS, Moore DD (January 1995). "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Mol. Endocrinol. 9 (1): 72–85. doi: 10.1210/mend.9.1.7760852 . PMID   7760852.
  7. ↑ Chuu CP, Kokontis JM, Hiipakka RA, Liao S (September 2007). "Modulation of liver X receptor signaling as novel therapy for prostate cancer". J. Biomed. Sci. 14 (5): 543–53. doi:10.1007/s11373-007-9160-8. PMID   17372849.
  8. ↑ Lou X, Toresson G, Benod C, Suh JH, Philips KJ, Webb P, Gustafsson JA (March 2014). "Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA". Nature Structural & Molecular Biology. 21 (3): 277–81. doi:10.1038/nsmb.2778. PMID   24561505. S2CID   23226682.
  9. 1 2 3 Hoerer S, Schmid A, Heckel A, Budzinski RM, Nar H (December 2003). "Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist". Journal of Molecular Biology. 334 (5): 853–61. doi:10.1016/j.jmb.2003.10.033. PMID   14643652. S2CID   43844694.
  10. ↑ Rühl R, de Lera AD, Krezel W (June 2015). "9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice". PLOS Genetics. 11 (6): e1005213. doi: 10.1371/journal.pgen.1005213 . PMC   4451509 . PMID   26030625.
  11. ↑ Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ (October 1996). "An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha". Nature. 383 (6602): 728–31. Bibcode:1996Natur.383..728J. doi:10.1038/383728a0. PMID   8878485. S2CID   4361170.
  12. ↑ Forman BM, Ruan B, Chen J, Schroepfer GJ, Evans RM (September 1997). "The orphan nuclear receptor LXRα is positively and negatively regulated by distinct products of mevalonate metabolism". Proc. Natl. Acad. Sci. U.S.A. 94 (20): 10588–93. Bibcode:1997PNAS...9410588F. doi: 10.1073/pnas.94.20.10588 . PMC   23411 . PMID   9380679.
  13. ↑ Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM (February 1997). "Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway". J. Biol. Chem. 272 (6): 3137–40. doi: 10.1074/jbc.272.6.3137 . PMID   9013544.
  14. ↑ Song C, Liao S (November 2000). "Cholestenoic acid is a naturally occurring ligand for liver X receptor alpha". Endocrinology. 141 (11): 4180–4. doi: 10.1210/endo.141.11.7772 . PMID   11089551.
  15. ↑ Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B (November 2000). "Role of LXRs in control of lipogenesis". Genes Dev. 14 (22): 2831–8. doi:10.1101/gad.850400. PMC   317060 . PMID   11090131.
  16. ↑ Herath KB, Jayasuriya H, Guan Z, Schulman M, Ruby C, Sharma N, MacNaul K, Menke JG, Kodali S, Galgoci A, Wang J, Singh SB (September 2005). "Anthrabenzoxocinones from Streptomyces sp. as liver X receptor ligands and antibacterial agents". J. Nat. Prod. 68 (9): 1437–40. doi:10.1021/np050176k. PMID   16180833.
  17. ↑ Edwards PA, Kennedy MA, Mak PA (April 2002). "LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis". Vascul. Pharmacol. 38 (4): 249–56. doi:10.1016/S1537-1891(02)00175-1. PMID   12449021.
  18. ↑ Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ (May 1998). "Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha". Cell. 93 (5): 693–704. doi: 10.1016/S0092-8674(00)81432-4 . PMID   9630215. S2CID   5856580.
  19. ↑ Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S, Ishibashi S, Yamada N (May 2001). "Identification of Liver X Receptor-Retinoid X Receptor as an Activator of the Sterol Regulatory Element-Binding Protein 1c Gene Promoter". Mol. Cell. Biol. 21 (9): 2991–3000. doi:10.1128/MCB.21.9.2991-3000.2001. PMC   86928 . PMID   11287605.
  20. ↑ Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ (November 2000). "Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ". Genes Dev. 14 (22): 2819–30. doi:10.1101/gad.844900. PMC   317055 . PMID   11090130.
  21. ↑ Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson JA (October 2002). "Liver X receptors in the central nervous system: From lipid homeostasis to neuronal degeneration". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13878–83. Bibcode:2002PNAS...9913878W. doi: 10.1073/pnas.172510899 . PMC   129791 . PMID   12368482.
  22. ↑ Andersson S, Gustafsson N, Warner M, Gustafsson JA (March 2005). "Inactivation of liver X receptor β leads to adult-onset motor neuron degeneration in male mice". Proc. Natl. Acad. Sci. U.S.A. 102 (10): 3857–62. Bibcode:2005PNAS..102.3857A. doi: 10.1073/pnas.0500634102 . PMC   553330 . PMID   15738425.
  23. ↑ Hafiane A, Gasbarrino K, Daskalopoulou SS (2019). "The role of adiponectin in cholesterol efflux and HDL biogenesis and metabolism". Metabolism: Clinical and Experimental . 100: 153953. doi:10.1016/j.metabol.2019.153953. PMID   31377319. S2CID   203413137.
  24. ↑ Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Björkhem I, Pettersson S, Gustafsson JA (March 2001). "Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice". J. Clin. Invest. 107 (5): 565–73. doi:10.1172/JCI9794. PMC   199420 . PMID   11238557.
  25. ↑ Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, Tran J, Tippin TK, Wang X, Lusis AJ, Hsueh WA, Law RE, Collins JL, Willson TM, Tontonoz P (May 2002). "Synthetic LXR ligand inhibits the development of atherosclerosis in mice". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7604–9. Bibcode:2002PNAS...99.7604J. doi: 10.1073/pnas.112059299 . PMC   124297 . PMID   12032330.
  26. ↑ Song C, Hiipakka RA, Liao S (June 2001). "Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis". Steroids. 66 (6): 473–9. doi:10.1016/S0039-128X(00)00239-7. PMID   11182136. S2CID   11199331.
  27. 1 2 Kratzer A, Buchebner M, Pfeifer T, Becker TM, Uray G, Miyazaki M, Miyazaki-Anzai S, Ebner B, Chandak PG, Kadam RS, Calayir E, Rathke N, Ahammer H, Radovic B, Trauner M, Hoefler G, Kompella UB, Fauler G, Levi M, Levak-Frank S, Kostner GM, Kratky D (February 2009). "Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia". J. Lipid Res. 50 (2): 312–26. doi: 10.1194/jlr.M800376-JLR200 . PMC   2636920 . PMID   18812595.
  28. ↑ Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, Saez E, Tontonoz P (April 2003). "Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5419–24. Bibcode:2003PNAS..100.5419L. doi: 10.1073/pnas.0830671100 . PMC   154360 . PMID   12697904.
  29. ↑ Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P (February 2003). "Reciprocal regulation of inflammation and lipid metabolism by liver X receptors". Nat. Med. 9 (2): 213–9. doi:10.1038/nm820. PMID   12524534. S2CID   10356659.
  30. 1 2 Anderson A, Campo A, Fulton E, Corwin A, Jerome WG 3rd, O'Connor MS (2020). "7-Ketocholesterol in disease and aging". Redox Biology. 29: 101380. doi:10.1016/j.redox.2019.101380. PMC   6926354 . PMID   31926618.
  31. ↑ Sanal MG (2008). "The blind men 'see' the elephant-the many faces of fatty liver disease". World J. Gastroenterol. 14 (6): 831–44. doi: 10.3748/wjg.14.831 . PMC   2687050 . PMID   18240340.
  32. ↑ Im SS, Osborne TF (April 2011). "Liver x receptors in atherosclerosis and inflammation". Circulation Research . 108 (8): 996–1001. doi:10.1161/CIRCRESAHA.110.226878. PMC   3082200 . PMID   21493922.
  33. ↑ Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS (February 2005). "The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease". J. Biol. Chem. 280 (6): 4079–88. doi: 10.1074/jbc.M411420200 . PMID   15557325.
  34. ↑ Fukuchi J, Kokontis JM, Hiipakka RA, Chuu CP, Liao S (November 2004). "Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells". Cancer Res. 64 (21): 7686–9. doi: 10.1158/0008-5472.CAN-04-2332 . PMID   15520170.
  35. ↑ Chuu CP, Hiipakka RA, Kokontis JM, Fukuchi J, Chen RY, Liao S (July 2006). "Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist". Cancer Res. 66 (13): 6482–6. doi: 10.1158/0008-5472.CAN-06-0632 . PMID   16818617.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.