Lecture 25: Liver Function Flashcards
Liver functions
- Exocrine: bile salts, bicarb
- Endocrine: insulin-like GF, angiotensinogen
- Plasma protein synthesis
- Metabolism (glucose, lipid synth., ketones, cholesterol)
- Excretion/degradation (heme, bile, cholesterol, bilirubin)
Hepatic blood supply
Systemic O2 from hepatic artery, GI blood from portal vein
Hepatic capillaries
Aka sinusoids; have fenestra that allow everything but cells to filter out to space of Disse/hepatocytes
ATP Binding Cassette Transporters
ABC transporters swap btwn open, inward facing/closed, outward facing conform.
ATP dependent swap; hydrolysis -> exchange, Nucleotide Binding Domain closure
Important liver ABCs
- ABC-B11: bile salt export @ canaliculus
- ABC-B4: phosphatidylcholine export @ canaliculus
- ABC-G5/8 heterodimer: sterols into bile/intestinal lumen
- ABC-C2: conjugated bilirubin to bile @ canaliculus
Non-ABC liver transporters
- Na-Taurocholate Cotransporter Protein (NTCP): Cotransport NA+, TC- into hepatocyte @ sinusoid
- Ileal Bile Acid Transporter (IBAT): bile salts to enterocytes
Bilirubin clearance
- Extra/intravascular hemolysis
- Unconjugated bilirubin + albumin to liver via blood
- Unconj. bilirubin + Z-protein (ligandin) + glucuronic acid in hepatocyte -> conj. bilirubin
- Excretion to s. intestine
- Digestion by bacterial proteases to urobilinogen
- 90% excrete in feces, 10% urobilinogen back to hepatocyte then to blood/urine
Hepatocyte bilirubin processing
- Carrier receptor uptake
- Bilirubin + ligandin -> bilirubin diglucuronide by glucoronyl transferase
- ABC-C2 export to bile canaliculus
Causes of hyperbilirubinemia (jaundice)
- Pre-hepatic
- Hepatocellular
- Post-hepatic
Pre-hepatic jaundice
Unconj. bilirubin defects:
- Overproduction (hemolysis)
- Transport (carrier defects)
Hepatocellular jaundice
Unconj. bilirubin defects:
- Conjugation (glucuronyl transferase defect)
Conj. bilirubin defects:
- Export (ABC-C2 defect)
Post-hepatic jaundice
Obstruction due to gall stone, cancer, stricture
Bile composition
90% bile acids, p-lipids, cholesterol; cholesterol is highly soluble in bile, insoluble in water
Bile acid synthesis
All made by liver from cholesterol:
Cholesterol to primary bile acids via 7α-hydroxylase (cholic + chenodeoxycholic acid)
Primary to secondary BAs via intestinal bacteria
Secondary to tertiary BAs via liver
Bile secretion mechanism (conj. bile salts NaTC, cholesterol, PC)
- NaTC-albumin uptake to hepatocyte via NTCP
- NaTC + IC binding protein in hepatocyte
- Cholesterol to primary BAs + taurine/Gly to NaTC-BP
- NaTC export via ABC-B11
- Cholesterol export via ABC-G5/8
- PC export via ABC-B4
All 3 components necessary for bile/micelle formation
Components of bile and their roles
Bile salts/acids: emulsify/solubilize P-lipids + chol.
P-lipids: membrane bilayers
Cholesterol: incorporated for mixed micelles
Exogenous lipid + lipoprotein metabolism + delivery
- Enterocyte resynth. TG -> chylomicra (Apo C/E/B48)
- Capillary LPL -> free FAs to adipose, muscle
- Chylomicron remnant reuptake by liver remnant receptor
Endogenous lipid + lipoprotein metabolism + delivery
- Liver synth. VLDLs (Apo B100)
- Capillary LPL -> free FAs to muscle/adipose -> IDL
- Hepatic lipase IDL -> LDL
- LDL uptake by LDLR in peripheral tissues
- Liver LDL/IDL uptake by LDLRs
Reverse cholesterol transport
- Peripheral cholesterol via ABC-A1 to nascent HDL
- Plasma LCAT (chol. -> CE) to HDL3 to HDL2
- HDL2 liver uptake by SRB-1 scavenger receptor to liver chol. pool (excretion in bile)
- Liver synth. Apo-A1 for nascent HDLs
