Molecular overview of progressive familial intrahepatic cholestasis

Abstract

Cholestasis is a clinical condition resulting from the imapairment of bile flow. This condition could be caused by defects of the hepatocytes, which are responsible for the complex process of bile formation and secretion, and/or caused by defects in the secretory machinery of cholangiocytes. Several mutations and pathways that lead to cholestasis have been described. Progressive familial intrahepatic cholestasis (PFIC) is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes. PFIC 1, also known as Byler's disease, is caused by mutations of the ATP8B1 gene, which encodes the familial intrahepatic cholestasis 1 protein. PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump (BSEP) expression via variations in the ABCB11 gene. Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein, leading to the third type of PFIC. Newer variations of this disease have been described. Loss of function of the tight junction protein 2 protein results in PFIC 4, while mutations of the NR1H4 gene, which encodes farnesoid X receptor, an important transcription factor for bile formation, cause PFIC 5. A recently described type of PFIC is associated with a mutation in the MYO5B gene, important for the trafficking of BSEP and hepatocyte membrane polarization. In this review, we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.

Keywords: ABCB11/bile salt export pump; ABCB4/multidrug resistance class 3; ATP8B1/familial intrahepatic cholestasis 1; Bile; Intrahepatic cholestasis; Progressive familial intrahepatic cholestasis.

Figure 1

Bile acid production. In phase 0, bile acids and other organic products are transported through the basolateral membrane of the hepatocyte. Phase I and II take place in the cytoplasm through activation and metabolization of differents CYPs. In phase III the bile acids are secreted into the biliary canalicus by the transmebrane transporters. NTCP: Na⁺-taurocholate cotransporting polypeptide; OATPs: Organic anion transporting polypeptides; OATs: Organic anion transporter; OCT1: Organic cation transporter 1; CYP7A1: Cytochrome P450 Family 7 Subfamily A Member 1; CYP8B1: Cytochrome P450 Family 8 Subfamily b Member 1; CYP27A1: Cytochrome P450 Family 27 Subfamily A Member 1; BSEP: Bile salt export pump; BRCP: Breast cancer resistance protein; ABCG5/8: ATP-binding cassette sub-family G member 5/8; MATE-1: Multidrug and toxin extrusion 1; MRP2: Multidrug resistance-associated protein 2; MDR1: Multidrug resistance class 1 glycoprotein; FIC1: Familial intrahepatic cholestasis 1; MDR3: Multidrug resistance class 3 glycoprotein; BC: Biliary canaliculus.

Figure 2

The molecular mechanisms behind progressive familial intrahepatic cholestasis. A: The classic types of Progressive Familial Intrahepatic Cholestasis (PFIC). PFIC 1 is related to mutations in the genes that encode the flippase familial intrahepatic cholestasis 1, which flips phospholipids in the plasma membrane. Mutations in the bile salt export pump (BSEP) protein, a bile salt transporter, results in PFIC 2. The third type of PFIC is caused by mutations in the gene that encodes the Multidrug resistance class 3 glycoprotein (MDR3) protein, another lipid flippase; B: The newer types of PFIC. Mutations in the tight junction protein-2 protein, which prevents the mixing of blood and bile acids, are responsible for PFIC 4. PFIC 5 is a result of mutations in the farnesoid X receptor protein, a transcription factor important for BSEP and MDR3 ecpression. Mutations in Myosin VB result in a PFIC phenotype because the trafficking of the BSEP protein from the endoplasmic reticulum to the plasma membrane is disrupted. PFIC: Progressive Familial Intrahepatic Cholestasis; FIC1: Familial intrahepatic cholestasis 1; BSEP: Bile salt export pump; MDR3: Multidrug resistance class 3 glycoprotein; TJP2: Tight junction protein-2; FXR: Farnesoid X receptor.