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Bile Acid Metabolism
Uni of Notts, Signalling & Metabolic Regulation, Year 2, Topic 14
| Term | Definition |
|---|---|
| Primary steroid hormone precursor conversion process | Cholesterol converted to pregnenolone in the adrenal cortex then to progesterone |
| Progesterone downstream hormone synthesis pathways | Progesterone undergoes progressive hydroxylation to yield androgens (androstendione can become testosterone or oestrogen; testosterone can become oestrogen), mineralocorticoids, & glucocorticoids |
| Vitamin D photolysis mechanism | Ultraviolet light reacts with 7-dehydrocholesterol to open its diene ring & form pro-vitamin D3 in the plasma membrane of epidermal keratinocytes & fibroblasts. This undergoes spontaneous thermal isomerization to cholecalciferol |
| Detergent properties of bile salts | Act as ionized salt detergents to physically disrupt dietary lipids & make them soluble for enzymatic breakdown |
| Intracellular toxicity & cholestasis | High intracellular concentrations dissolve hepatocyte membranes & organelles, inducing toxic liver cholestasis |
| Metabolic nuclear signalling targets for bile acids | Behave as active signalling molecules via nuclear receptors to regulate lipid metabolism, glucose pathways (PEPCK & G6Pase), & energy expenditure (thyroid hormones) |
| Gallbladder storage composition | The gallbladder stores bile containing a mixture of bile acids, phospholipids, cholesterol, & bilirubin (waste product of discarded red blood cells & is an antioxidant) |
| Primary human bile acids + general composition | Cholic acid (CA) & chenodeoxycholic acid (CDCA) in equal amounts. Both are cholesterol with a carboxylated side-chain & extra hydroxyl but CA has an additional hydroxyl group compared to CDCA |
| Neutral pathway initiation & modification steps | Main hepatic pathway, cholesterol 7α-hydroxylase converts cholesterol into 7α-hydroxycholesterol. Then ring structure modification, side chain oxidation, & terminal amino acid conjugation |
| The Acidic (Alternative) Bile Acid Pathway | A minor synthesis pathway in peripheral tissues (blood, lymph) & macrophages using oxysterols as substrates. Intermediates transported to the liver for final modification, the pathway mainly yields chenodeoxycholic acid (CDCA) |
| Amino acid conjugation partners | Primary bile acids are conjugated with glycine or taurine to produce glycocholate or taurocholate (G/T-CA) |
| Bacterial conversion to secondary acids | Anaerobic gut bacteria use 7α-dehydroxylase to strip hydroxyl group from primary conjugated bile salts, making very hydrophobic secondary bile acids exhibiting distinct membrane-disrupting properties (e.g., deoxycholate, CDCA, & lithocholic acid (LiCA) |
| Reabsorption efficiency statistics of bile acids | ~98% of secreted bile acids are actively reabsorbed, while only 2% are lost via fecal excretion |
| Reason why we have the fecal excretion route | Essential because animal cells completely lack the metabolic machinery to break the steroid ring skeleton down into CO2 & H2O & need to remove steroids |
| Bile acid sequestrant mechanics | Therapeutic polymers exchange anions (e.g., Cl-) for bile acids which traps them & prevents reabsorption so they will be excreted from the body |
| Transcriptional response element zones for bile acids & key genes | Target genes like CYP7A1 (cholesterol 7α-hydroxylase, main regulatory step in neutral pathway) & CYP8B1 (Cytochrome oxidase P450 monooxygenase) contain specific Bile Acid Response Elements (BAREs) to anchor active transcription factors |
| Human versus rodent nuclear receptors | Both: Farnesoid X Receptor (FXR), binds CDCA, negative feedback loop Human: Liver Receptor Homologue-1 (LRH-1), maintains base CYP7A1 except in high bile salt Rodent: Liver X Receptor (LXR), drives CYP7A1 transcription in high cholesterol to clear it |
| P450 cytochrome enzymes | Used haem group to form a ROS to oxygenate or hydroxylate molecules such as squalene to an epoxy or cholesterol to other molecules. Reduces the other oxygen to water with NADPH |
| Retinoid X Receptor dimer formation | Regulatory nuclear receptors must form active obligate heterodimers with Retinoid X Receptor to coordinate DNA binding |
| FXR activation ligand specificity | Activated directly by many bile acids, with chenodeoxycholic acid serving as its highest affinity natural ligand |
| Small Heterodimer Partner (SHP) pathway | Atypical nuclear receptor lacking DNA-binding domain. Acts as a co-repressor, directly binds to & inactivates LRH-1, preventing it from transcriptionally upregulating CYP7A1 (rate-limiting enzyme) |
Created by:
Denny12
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