Hormones Peptide HormonesSteroid Hormones

Examples of Lipophillic Hormones

Development of radio-labeled ligands which lead to the identification of proteins, which were shown to translocate from cytoplasm to nucleus Steroids were shown to be targeted to their receptor proteins 2.Receptor proteins were shown to bind genomic sites cDNAs encoding the glucocorticoid and estrogen receptors was identified. These were the first transcription factors for RNA polymerase II 2.Discovery of receptors for the vitamin A metabolite, retinoic acid- solidified the existence of a nuclear receptor superfamily Identification of receptors for all known nuclear hormones and also identification of orphan receptors 2000-Physiological role of orphan nuclear receptors

Nuclear Receptors Known Ligands Unknown Ligands (Orphan )

Structure of Nuclear Receptors Classes of Nuclear Receptors

Nuclear Receptor Superfamily

Physiological Role of LXRα

LXR α and Cholesterol Metabolism

LXRα and Atherosclerosis Low-density lipoproteins (LDL) High-density Lipoproteins (HDL ) Coronary artery disease

LXRα Agonists have Beneficial Effects on Cholesterol Homeostasis

LXR α and Lipogenesis

LXR RXR Lipogenic gene promoter Direct pathway SRELXRE Srebp-1c promoter SREBP-1c Indirect pathway LXRE LXRα Agonists Induces Fatty Acid Synthesis

Liver X Receptor- β 1.Cloned by four separate groups a) RIP-15 (Seol et al., 1995) b) OR1 (Teboul et al., 1995) c) NER (Shinar et al., 1994) d) UR (Song et al., 1194) 2. LXRβ and LXRα shares 77% sequence identity in amino acids 3. LXRβ is constitutively expressed at low level in all tissues 4. LXRβ/RXRα heterodimers bind to a modified LXRE 5. LXRβ is activated by N-Acylthiadiazolines

Physiological Roles of LXRβ 1.LXRβ -/- were resistant to weight gain and malabsorption syndrome due to chronic pancreatitis a) reduction in serum levels of α-amlyase and lipase b) Immune infiltrations of pancreatic duct c) Increased rate of epithelial cell death d) formation of laminar structure e) Increase expression of aquaporin-1, a water channel transporting water into the pancreatic lumen 2. LXRβ -/- mice at seven months of age develop motor impairment compared to WT a) Loss of large α-motor neurons b) Accumulation of lipid in the cytoplasm of neurons and protein aggregation stained for TDP-43 and ubiquitin-features typical of amyotrophic lateral sclerosis

3. LXRβ -/- mice had smaller brains compared to WT-reduction in the number of neurons 4.

Glass and Rosenfeld Transcriptional Activities of Nuclear Receptors

LXRs and Cholesterol Metabolism