Hepatic Cholestasis

non-sulfated & sulfated bile salt cholesterol esters non-bile organic anions organic anion transporting polypeptide OATP

non-bile organic anions microsomal epoxide mEH hydrolase

bile salts (bile acid conjugates)

h e p a to cy te sinusoida l mem bran e

Na+/bile acid/ NTCP cotransporter transcription

ABCC1 (Mrp1)

LPS & IL-1 Inhibit RXR Protein Function
JNK curcumin

ABCC4 (Mrp4)

ABCC3 (Mrp3)

LPS

+
LPS
bile salts

+
transcription biliary cirrhosis MRP-2 disfunction cholestasis

LPS

bile salts

+
retinoic acid RAR RXR c-Jun GW-4064

dexamethasone

Cholesterol Biosynthesis Fatty Acid Biosynthesis
SREBP-1c LDLR LDL receptor increased mRNA stability MEK triglyceride-rich lipoprotein CETP cholesterol ester transport protein

LRH-1 steroid hormone receptor homolog transactivation polyunsaturated fatty acid

transcription SHP small heterodimer + partner (transcription repressor) RXR FXR c-Jun JNK bile [salts ]

+ +
transcription

+ oxidized sterols
cholesterol-27hydroxylase CYP27 CYP7A1 ?

transcription

side chain

Cl Cl - /HCO 3 - exchanger AE2

ABCB4 (Pgp2,MDR2)

HCO 3 phospholipid

ABCC2 (Mrp2)

h e p a t o c y t e c a n a l i c u l a r membran e

bile salt export pump ABCB11 (BSEP)

ABCB1a (MDR1a) (Pgp3)

non-bileorganic anion (GSH, bilirubin...)

bile salt
Copyright

drugs & xenobiotics
C

2006 Iconix Biosciences Inc.

+

LPS

cholesterol

Hydroxylated lithocholic acids

LPS
ABCB1b (MDR1b) (Pgp1)

+

cholesterol ester (on HDL)

+ +

chenodeoxycholic acid
partial agonist

intestinal bacterial enzyme

(very hydrophobic)

lithocholic acid

+
transcription RXR PXR

+
CYP3A

pregnenolone progesterone
barbiturates glucocorticoids rifampin troglitazone nervirapine

+

metaboloized drugs, xenobiotics

LPS

Sign up to vote on this title
UsefulNot useful