Cholesterol and Bile Acid Metabolism - Abali 2/22/16 Flashcards
composition of hepatic and gallbladder bile
bile acid
phospholipid
cholesterol
bilirubin (0.3%)
protein
summary of bile action in digestive system
- synthesized from cholesterol in liver
when you have a fatty meal, CCK released by endocrine cells
- contracts gallbladder
- opens sphincter of Oddi, releasing bile into duodenum
bile is a detergent (it can solubilize fats/oils) → bile acids/salts form micelles with ingested lipids
- micelles are digested by lipases and/or made into chylomicrons
bile salts absorbed in ileum, move back to liver via hepatic portal vein
properties of bile acids and salts
why is this important?
- planar
- amphipathic (hydrophilic/phobic)
- philic: all COOH and OH groups on one side
allows lipids to packaged in a way that lets them be transported in blood and sequesters them for lipase to go to work
cholesterol and role of liver in processing
- chol is NOT required in diet (bc we can make it through de novo synth)
- sources: dietary and de novo synthesis (mostly liver but also extrahepatic tissues)
- liver is major regulator of chol metabolism
- exports it in VLDL
- coverts it into bile acids/salts
- excretes it in bile
**cholesterol can only be excreted via bile acids/salts and bile in feces
cholesterol excretion
can’t degrade it to water and CO2 (no way to break it down to component parts)
- either make it into other stuff (vitamin D, steroid hormones) or eliminated in feces as…
- unmodified chol
- bile acids
- reduced chol (5% thats not picked back up into portal circ reduced via bacteria into cholestanol, coprostanol)
primary and secondary bile acids
liver takes cholesterol, hydroxylates it to make primary bile acids (later modified via conjugation), which are then deconjugated/dehydroxylated by intestinal bacteria to become secondary bile acids
- cholic acid → deoxycholic acid
- chenodeoxycholic acid → lithocholic acid
committed step in bile acid synthesis [enzyme]
7-alpha hydroxylase
cytochrome P450 enzyme
- *CYP7A**
- shortens a side chain/adds a COO, reduces a double bond, adds OH at 7 and 12 positions to make…*
cholesterol → cholic acid
regulation via
- substrate activation: cholesterol activates
- product inhibition: cholic acid inhibits
CYP 7A
cytochrome P450 enzyme: 7alpha hydroxylase
regulates committed step in bile acid synthesis
shortens a side chain/adds a COO, reduces a double bond, adds OH at 7 and 12 positions to make…
cholesterol → cholic acid
regulation via
- substrate activation: cholesterol activates
- product inhibition: cholic acid inhibits
difference between cholic acid and chenodeoxycholic acid
both primary bile acids (CYP7A key in synth)
cholic acid: 3 OH groups (3, 7, 12 positions)
chenodeoxycholic acid: 2 OH groups (3, 7 positions)
synthesis of bile acids from cholesterol
catalyzed by CYP 7A
- OH groups added
- side chain shortened, COO group added
- double bond reduced
chenodeoxycholic acid lacks the C12 OH
primary bile acids are modified through conjugation
- define
- why?
bile acids are emulsifiers, so we want them to be more charged so as to be better detergents
- → cholyl CoA (pKa 6)
- conjugation with glycine or taurine (made from Cys) lowers the pKa of bile acids
- taurocholic acid/taurochenodeoxycholic acid (pKa 2)
- glycocholic acid/glycochenodeoxycholic acid (pKa 4)
conversion of primary bile acids (conjugated) to secondary bile acids
bacterial transformation (in intestine)
- deconjugation → cholic/chenodeoxycholic acid
- dehydroxylation at C7 → deoxycholic/lithocholic acid
makes them more insoluble
- some absorbed through hydrophobic cell membranes
- most released in feces
biliary bile acids [
vs
fecal bile acids
biliary bile acids leaving liver are virtually all conjugated
fecal bile acids are virtually all unconjugated
bile acids vs bile salts
interchangeable terms - depends on whether they still have their proton (acids) or not (salts)
conjugated bile acids
- glycocholic acid
- glycochenodeoxycholic acid
- taurocholic acid
- taurochenodeoxycholic acid
predominate in biliary bile acids (in bile duct)
unconjugated bile acids
- cholic acid
- chenodeoxycholic acid
- deoxycholic acid
- lithocholic acid
predominate in fecal bile acids (in intestine)
enterohepatic circulation
- percentages
- link to chol
- approx 95% of conjugated bile acids: reabsorbed in distal ileum, returned to liver via portal vein (enterohepatic circulation)
- remaining 5%: move into → secondary bile acids
- eventually lost in feces
- since bile acids/salts originate from cholesterol, this is the way the body excretes cholesterol
0.5 g excreted daily (out of approx 15-30 g secreted)
BAS
- definition
- mech of action
- application, ex
bile acid sequestrant/resin
- bind to bile acids, prevent them from being reabsorbed in intestine
- forces liver to up the synth of bile acids (i.e. use up stores of chol, take up more chol from plasma)
application
liver upregulates LDL receptor, effectively decreases LDL in circulation!
- cholestyramine (Questran)
- colesevelam (Welchol)
- colestipol (Colestid)
major bile acid transporters in enterohepatic circulation
hepatocyte to bile canaliculus:
BSEP (bile acid export pump) - ATP dependent
- bile does its thing from duodenum on into ileum
from int lumen into/through distal ileal cell into portal circ:
ASBT (apical Na-dep bile acid transporter) - Na dep
OSTalpha-OSTbeta (basolateral organic solute and steroid transporter)
- 95% of bile absorbed in distal ileum moves through portal vein and up into liver sinusoids
from sinusoids into hepatocytes:
NTCP (Na-dep taurocholate cotransporting polypeptide) - Na dep
OATP (organic anion transporting polypeptides)
- 5% of bile that moves into colon either taken up (v small fraction) or excreted in feces
cholelithiasis
formation of gallstones (more yellowish) via crystallization of cholesterol in bile
- happens when you have extra chol secretion into biliary tract
caused by…
- severe ileal disease: reduced enterohepatic circ: increased fraction of chol in bile (bc CYP7A can’t keep up with demand)
- bile duct obstruction
- severe hepatic dysfunction: messes with liver enzymes
- genetic susceptibility (LITH genes)
conditions in which gallstones favored
proportions of phosphatidylcholine/lecithin (phospholipid), bile salts, and chol determines the solubility of chol in bile
more gallstones if you:
reduce PL
reduce bile
increase chol
formation of gallstones in biliary tree
- locations
- assoc symptoms
1. in cystic bile duct
- painful gallbladder contractions
2. blocking common bile duct
- no bile release into duodenum
- failure to digest fats → steatorrhea, diarrhea
- gray feces (no bile pigments)
- failure to excrete bilirubin → jaundice
3. blocking duodenal papilla
- no bile/pancreatic secretion release into duodenum
- serious malnutrition (can’t digest chyme)
- acute pancreatitis
morphological features of cholestasis
everything gets BIG for diff reasons
- cholestatic hepatocytes are enlarged
- bile canaliculus enlarged
- Kupffer cells (macrophages in hepatocytes) engulf excess bile - seen with bile pigments
- cell apoptosis
excess bile blocks stuff up
- bile plugs in bile ducts
steatorrhea
fat in feces due to malabsorption in intestines
Zollinger Ellison syndrome
gastrin-secreting tumor or hyperplasia of the islet cells in the pancreas causing overproduction of gastric acid, resulting in recurrent peptic ulcers
dumping syndrome
weakness, abdominal discomfort, and sometimes abnormally rapid bowel evacuation, occurring after meals in some patients who have undergone gastric surgery
