Hepatocellular transport proteins and their role in liver disease

Table 1 Role of hepatocellular transport proteins in the pathogenesis of liver disease

Species	Transport protein	Gene symbol	Physiologic function	Alteration in liver disease
Basolateral transport proteins
Rat/human	Ntcp/NTCP	SLC10A1	Na+ dependent bile salt uptake	Decreased Ntcp expression in rat models of cholestasis[25,26,34]
				Decreased NTCP expression in human cholestatic liver disease[35]
Rat	Oatp1	Slc21a1	Multispecific uptake of organic anions	Decreased Oatp1 expression in bile duct ligation[32] and in ethinyl
			and amphipathic compounds	estradiol induced cholestasis[34]
	Oatp2	Slc21a5	Multispecific uptake of organic anions	Not yet investigated
			and of cardiac glycosides (digoxin)
	Oatp4	Slc21a10	Multispecific uptake of organic anions	Decreased Oatp4 expression in bile duct ligation and sepsis[59]
			and amphipathic compounds
Human	OATP-A	SLC21A3	Multispecific uptake of organic anions	Increased mRNA levels in primary sclerosing cholangitis (PSC)[180]
			and amphipathic compounds
	OATP-B	SLC21A9	Multispecific uptake of organic anions	Not yet investigated
			and amphipathic compounds
	OATP-C	SLC21A6	Multispecific uptake of organic anions	Decreased mRNA levels in primary sclerosing cholangitis[181]
			and amphipathic compounds	Not yet investigated
	OATP8	SLC21A8	Multispecific uptake of organic anions
			and amphipathic compounds
Rat/human	rOCT1/hOCT1	SLC22A1	Uptake of small hydrophilic organic	Not yet investigated
			cations (TEA, MPP, choline, dopamine)
Rat	OAT2	SLC22A7	Uptake of glutarate, salicylates,	Not yet investigated
			methotrexate, PGE2 and PAH
Rat	OAT3	SLC22A8	Uptake of PAH, estrone-3-sulfate,	Not yet investigated
			ochratoxin A, cimetidine
Rat/human	Mrp1/MRP1	ABCC1	Efflux of cytotoxic cations and	Increased expression in hepatoma cells[85] and sepsis[182]
			non-bile salt organic anions
Rat/human	Mrp3/MRP3	ABCC3	Efflux of organic anions, bile salts	Increased Mrp3 expression in Eisai Hyperbilirubinemic Rats and
			and anticancer agents	in bile duct ligation[91]
				Increased MRP3 expression in Dubin-Johnson syndrome and
			primary biliary cirrhosis[86]
Rat/human	Mrp6/MRP6	ABCC6	Efflux of BQ-123	Not yet investigated
Canalicular Transport Proteins
Mouse/rat/mBsep/Bsep/BSEP		ABCB11	Canalicular efflux of bile salts	Mutations in the BSEP gene and absence of the protein in patients
Human				with PFIC2, characterized by low γ -GT levels and reduced biliary
				bile acid excretion[103,110]
				Cis-inhibition by cholestatic drugs such as cyclosporine A[172]
				Trans-inhibition by the cholestatic estrogen metabolite estradiol-
				17β− D-glucuronide[172,175]
				Increased mBsep expression in C57L/J gallstone-susceptible
				mice, despite reduced bile salt excretory capacity[107,109]
Mouse/rat/	Mdr2/Mdr2/MDR3	ABCB4	Biliary excretion of phospholipids	Mdr2-/- knockout mice exhibit an absence of phospholipids in bile
				and develop progressive liver disease with portal inflammation,
				bile duct proliferation and fibrosis[123]
				PFIC3, characterized by high γ -GT levels and absent lipoprotein
				X in serum, is caused by mutations in the MDR3 gene
				(chromosome 7q21)[143]
				MDR3 mutations in PFIC3 are associated with intrahepatic
				cholestasis of pregnancy[171]
Rat/human	Mrp2/MRP2	ABCC2	Canalicular excretion of organic anions	Decreased Mrp2 mRNA and protein levels in bile duct ligation and
				endotoxinemia[154,183]
				Decreased canalicular density of Mrp2 transporter molecules in
				endotoxinemia[183], taurolithocholate cholestasis[184]
				and bile duct ligation[154]
				Mutations in the rat Mrp2 gene cause hereditary conjugated
				hyperbilirubinemia[112]
				Mutations in the human MRP2 gene cause the Dubin-Johnson
				syndrome with absent protein expression[147,149]
				MRP2 function is inhibited by anabolic 17á-alkylated
				steroids[185,186]
				Decreased MRP2 mRNA but unchanged protein levels in PBC[187]
				Decreased MRP2 mRNA levels in PSC[181]
Human	FIC1	ATP8B1	Putative aminophospholipid	P-type ATPase, positional candidate in genetic linkage analysis of
			translocator	PFIC1 (Byler’s disease) and BRIC[141]
Human	AE2	SLC4A2	Canalicular Cl-/HCO3- exchange	DecreasedAE2 expression on the luminal surface of cholangiocytes in
				PBC (increased expression secondary to UDCA treatment)[188]

Abbreviations: Ntcp/NTCP, rat/human Na⁺-taurocholate cotransporting polypeptide; Oatp/OATP, rat/human organic anion transporting polypeptide; rOCT1/hOCT1, rat/human organic cation transporter 1; OAT, organic anion transporter; Mrp/MRP, rat/ human multidrug resistance protein; mBsep/Bsep/BSEP, mouse/rat/human bile salt export pump; Mdr/MDR, rodent/human multidrug resistance gene product; FIC1, familial intrahepatic cholestasis protein; AE2, anion exchanger 2; PSC, primary sclerosing cholangitis; PFIC, progressive familial intrahepatic cholestasis; PBC, primary biliary cirrhosis; BRIC, benign recurrent intrahepatic cholestasis; UDCA, ursodeoxycholic acid.