Mod 1 Oxysterols

Question 1

when are oxysterols produced?

Answer 1

during cholesterol synthesis and transformation of cholesterol into other metabolites (AKA steroid and bile acid metabolites)

Question 2

Oxysterols regulate via which type of receptor?

Answer 2

LXR nuclear receptor (type II, RXR heterodimer)

Question 3

Oxysterols biological activities

Answer 3

• Sterol efflux from cells (ABCA1 transporter)
• Bile acid and steroid hormone synthesis (Cyp7a1)
• Transcription regulation of lipid metabolism via LXR and SREBP’s Insig
• Control of lipid metabolism and transport (OSBP/ORP)
• Modulation of estrogen receptor function
• Pro-inflammatory signaling
• Cytotoxic and pro-apoptotic effects
• Hedgehog signaling - induction of cell differentiation

Question 4

LXR types and functions

Answer 4

LXR alpha - expressed in liver and cells important in lipid metabolism
ex. liver, intestines, adipose tissue and macrophages

LXR beta - ubiquitous distribution

Question 5

LXR binding variation

Answer 5

LXR are nuclear receptors bound by oxysterols

Genetic differences can effect how well an LXR variant can bind

Alpha and beta are similar in structure and likely have some overlap of sequences they can bind

Question 6

LXR binding pathway

Answer 6

LXR forms a heterodimer with RXR

Oxysterol ligand presence converts corepressor into coactivator which binds heterodimer (along with RA)

(Will work without RA but not as well)

Question 7

Genes regulated by LXR

Answer 7

ABCA1 - efflux of cholesterol from cells

Cyp7a1 - RLS of bile acid synthesis in mice (cholesterol 7-alpha hydroxylase)

SREBP-1c - regulation of genes involved in fat metabolism
ex. steroyl co-A desaturase in TAG biosynthesis