Liver X receptor

The liver X receptor (LXR) is a member of the

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

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]

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 ų and T-0901317 easily positions itself with a molecular volume of 304 ų. 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

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.

• ABC – ATP Binding Cassette transporter isoforms A1, G1, G5, and G8
• ApoE – Apolipoprotein E
• CETP
  – CholEsterylester Transfer Protein
• FAS – Fatty Acid Synthase
• CYP7A1
  – CYtochrome P450 isoform 7A1 - cholesterol 7α-hydroxylase
• 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
• ChREBP
  – Carbohydrate Regulatory Element Binding Protein

Role in metabolism

The importance of LXRs in physiological

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

Potential therapeutic applications of LXR agonists

LXR

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

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]

References