1. Hormones Peptide HormonesSteroid Hormones

2. Examples of Lipophillic Hormones

3. 1960 -70Development of radio-labeled ligands which lead to the identification of proteins, which were shown to translocate from cytoplasm to nucleus 1970-801.Steroids were shown to be targeted to their receptor proteins 2.Receptor proteins were shown to bind genomic sites 1980-901.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 1990-2000Identification of receptors for all known nuclear hormones and also identification of orphan receptors 2000-Physiological role of orphan nuclear receptors

5. Nuclear Receptors Known Ligands Unknown Ligands (Orphan )

6. Structure of Nuclear Receptors Classes of Nuclear Receptors

7. Nuclear Receptor Superfamily

21. Physiological Role of LXRα

22. LXR α and Cholesterol Metabolism

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

24. LXRα Agonists have Beneficial Effects on Cholesterol Homeostasis

25. LXR α and Lipogenesis

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

29. 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

31. 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

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

34. Glass and Rosenfeld Transcriptional Activities of Nuclear Receptors

37. LXRs and Cholesterol Metabolism