In normal conditions, ATP-binding cassette, subfamily B, member11 (ABCB11
) and other hepatobiliary proteins (i.e., ABCG5/8- and ABCB4-transporting sterols and phospholipids into bile, respectively) maintain appropriate concentrations of biliary components.
On the other hand, 22 SNPs were exclusively related to a specific lipid--4 for TC: rs569805 (ABCB11
), rs494874 (ABCB11
), rs1801260 (CLOCK), andrs6013029 (CTNNBL1); 3 for LDL-c: rs7799039 (LEP), rs7498665 (SH2B1), and rs7359397 (SH2B1); 9 for HDL-c: rs2815752 (NEGR1), rs-2943641 (IRS1), rs2419621 (ACSL5), rs6265 (BDNF), rs110-30104 (BDNF), rs4769873 (ALOX5AP), rs9939609 (FTO), rs6567160 (MC4R), and rs2287019 (QPCTL); and 6 for TG: rs324420 (FAAH), rs2959272 (PPARG), rs1386835 (PPARG), rs709158 (PPARG), rs1175540 (PPARG), rs1800544 (ADRA2A) (Figure 1).
BSEP, encoded by ABCB11
, is responsible for the ATP-dependent transport of predominantly monovalent conjugated BS across the hepatocyte canalicular membrane.
Other pharmacogenomic associations include HLA-B* 59:01 and methazolamide-induced SJS/TEN in Koreans and Japanese , HLA-B* 73:01 and oxicam-induced SJS/TEN in Europeans , and ABCB11
, C-24T, UGT2B7*2, and IL-4 C-590-A and diclofenac-induced liver disease in Europeans [109, 110].
Familial intrahepatic cholestasis (FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11
Therefore, hereditary CLD in children, which result from mutations of genes involved in bile acid and phosphatidylcholine transport, such as ATP8B1 [4, 5], ABCB11
, and ABCB4 , are relatively easy to diagnose.
ABCB4 and ABCB11
mutations in intrahepatic cholestasis of pregnancy in an Italian population.
Bile salt export pump (BSEP) is a liver-specific ATP-binding cassette transporter encoded by the ABCB11
gene, which is expressed exclusively in the liver canalicular membrane and involved with bile acid transport.
La colestasis 1 (CIFP1), enfermedad intrahepatica familiar, cuya fisiopatologia esta aun bajo investigacion; corresponde a una enfermedad de la bomba de exportacion (BSEP) que resulta en un defecto en la excrecion canalicular de acidos biliares secundaria a una mutacion en el gen ABCB11
. La colestasis 3 (CIFP3), es una deficiencia de la proteina multifarmaco-resistente 3 (MDR3) con defecto en la excrecion canalicular de fosfolipidos (2).
Loss of function mutations in ABCB11
has been identified in patients with PFIC type 2 (PFIC2), typically resulting in absence of hepatic BSEP expression [26, 27].
Two ABC transporters involved, which are expressed on the canalicular membrane of hepatocytes: the bile salt export pump (BSEP, also called ABCB11
) [32, 33] and the multidrug resistance protein (MDR) (MDR-3 in humans and MDR-2 in mice (ABCC2)) , are also FXR targets.
In addition to above described mechanisms, miR-33 targets ABCB11
and ATP8B1, both of which are important molecules in cholesterol efflux into biliary ducts; this targeting thus supports cholesterol retention caused by the upregulation of SREBP and miR-33 in hepatocytes .