heme catabolism and bile salt Flashcards
during heme catabolism the body has to deal with
handling the hydrophobic products of the porphyrin ring cleavage, and retention, safe mobilization and reutilization of iron
A macrophage: heme ring opening, heme–> biliveridin–> bilirubin
In the blood albumin carries bilirubin from the macrophage to liver
Liverhepatocytes conjugate bilirubin with glucuronic acid and it becomes excreted
GIT: conjugated bilirubin is converted by bacteria, removal of glucuronic acid, conversion to urobilinogen
Kidney conversion of urobilinogen to urobilin–>urine
heme catabolism
heme is degraded in a series of reactions to produce bilirubin which is normally excreted into bile by the liver
jaundice/icterus: accumulation of elevated bilirubin in the skin, sclera, imparing a yellow color, inherited disorders of bilirubin metabolism lead to hyperbilirubinemia
senescent RBCs taken up by Macrophages in the reticuloendothelial system of the liver and spleen
Bilirubin (orange)- toxic freeform, harmless when bound to albumin
Heme oxygenase is the first and rate limiting step and cleaves the ring (with NADPH, O2, cyt p450 OR)–iron and CO–> biliverdin (green)
HO1- inducible, HO2- constitutive
Biliveridinreductace takes biliveridin –> bilirubin yellow
bilirubin is released into the blood and carried via albumin to the liver
uptake, storage, conjugation and excretion in liver
Hepatocyte: bilirubin is taken from albumin then enters the hepatocyte, once inside bilirubin is kept in cytosol via liagandins, ligandin binds both conjugated and unconjugated bilirubin
unique function of the liver is the ability to conjugaet bilirubin with glurcuronic acid
Unconjugated bilirubin is nonpolar/lipiphilic, conjugated can be excreted vi bile canaliculus (via esterification of propionic acid carboxyl groups)
Glucioronic acid is the major conjugating group and the reaction is catalyzed by Uridine diphosphate glucuronosyltransferase (UGT1A1) in the hepatocyte ER
One or 2 Glucuronic acids are added :mono BMG or Di- BDG
Energy dependent process, MDAT (atp dependent), allows for membrane excretion
heme catabolism in intestinal bacteria
Bilirubin (conjugated) goes to intestine, degraded into urobilinogen without conjugation and is uncolored
intestinal bacteria also oxidize urobilinogen to make stericobilin which gives poop its brown color
urobilinogen is reabsorbed–> kidney and peed out giving urine its yellow color
disorders of bilirubin metabolism
the hepatic processing of bilirubin has 4 stages:
- uptake from the circulation
- intracellular binging and storage
- conjugation
- biliary excretion
any issue with these: hyperbilirubinemia/jaudice
Disorders of the unconjugated and disorders og the conjugated type
Clinical lab test for serum bilirubin
total bilirubin= can make you jaundiced
vanden bergh assay tells you if its conjugated or unconjugated that is increased
Only water soluble (conjugated) bilirubin reacts rapidly–> direct bilirubin
Unconjugates/ insoluble reacts slowly
Methanol reaction gives total bilirubin
Indirect (unconjugated) is calculated from total- direct
Indirect=unconjugated, direct= conjugated
Unconjugated Hyperbilirubinemia
AKA Neonatal jaundice
every newborn has hyperbilirubinemia due to delayed maturation of the liver, about half become jaundiced in the first 5 days due to:
Low activity of UGT1A1, decreased capacity of hepatocytes, increased bilirubin production secondarry to destruction of fetal RBC during birth process
Serum bilirubin is mostly unconjugated in baby, untreated–> basal ganglia damage–> muscle movement issues
Kernicterus - bilirubin encephalopathy–> athetoid (writhing) cerebral palsy and deafness
Usually neonatal jaundice is inocuous and antioxidant for lipid peroxidation
Treated with phototherapy to make unconjugated bilirubin more excretable
Inherited unconjugated hyperbilirubinemia
disorders in UGT 1A1 expression–> lowered hepatic conjugataion of bilirubin
Gilbert syndrom most common and least sever (benign usually)
Crigler Najjar 1 most severe: no UGT1A1- kernicteris
Crigler Najjar 2: very low UGT1A1
conjugated hyperbilirubinemia
Defects of bilirubin secretion, inherited. Dubin Johnson (MOAT defect), Rotor
Hepatocytes cant secrete the conjugated bilirubin into the bile canalicili, and instead returns to blood
other causes of jaundice
Hemolytic (increased indirect/unconjugated)- excessive RBC destruction leads to bilirubin in excess of conjugating ability of liver (and excretion into bile), free bilirubin increases in plasma as a result
Obstructive (increased direct/conjugated)- partial/complete block of bile duct, cant be excretted into intestine so goes into plasma
Hepatocellular (increased indirect/unconjugated)-damage to the liver by toxins, poisons, cardiac failure etc impairs the livers capacity to conjugate and excrete
cholesterol is the precursor of bile acids
bile acids synthesized from cholesterol in the liver, bile acids are secreted into bile canaliculi, which are specialized channels formed by adjacent hepatocytes
Bile acids go to gallbladder for storage and ultimately to small intestine where theyre excreted
Bile acids - emulsifying agents, aggreagate into micelles to prepare dietary TGs for hydrolysis by pancreatic lipase, absorption of vitamins such as Vit D
Bile acids are endocrine molecules that signal thru specific bile acid activated nuclear (FXR) and membrane bound receptors (TGR5)
Cholesterol is excreted primarily as bile acids
cholesterol is converted into CHOLIC ACID (soluble), via 7a-HYDROXYLASE
in the liver, most bile acids are derivatives of cholic acid,
The only way to excrete plasma mem cholesterol is via free cholesterol and bile acids
bile
primary bile acids are synthesized in hepatocytes directly from cholesterol (cholic acid and chenodeoxycholic acid)
Primary acids are converted to secondary bile acids by bacteria in the gut via dehydroxylation reaction (deoxycholic acid and lithocholic acid)
bile salts: 1’ and 2’ bile acids are reabsorbed by the intestine (ileum) into the portal blood and taken up by hepatocytes where they are conjugated to glycine or taurine to make bile salts- making it a stronger acid and more soluble
familial hypercholestrolemia
elevated LDL in plasma, LDL is deposited in tendons and skin and arteries, AD, gene dosage effect, LDLreceptor is mutated
Heterozygotes
Liver requires cholesterol to make bile
HMG Co A reductase inhibitors decrease LDL
Bile acid binding resins (Cholestyramin and colestipol bind bile in the lumen and prevent their recycling
