Regulation of bile acid transport: Beyond molecular cloning

✍ Scribed by Jonathan A. Dranoff; Michael H. Nathanson

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 28 KB
• Volume: 29
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510290643

✦ Synopsis

ous Saudi Arabian families. 10 A rat SPGP cDNA was used to isolate a human orthologue of SPGP. The human SPGP and the FIC2 locus were found to lie in an 870-kb yeast artificial chromosome insert. PFIC patients in whom the pattern of marker inheritance was consistent with linkage to chromosome 2q24 were screened for mutations in the SPGP coding sequence. The investigators in these initial studies found 10 mutations with a number of predicted changes in protein structure. Four of the mutations predicted premature truncation of the protein. Two different C to T transitions, which resulted in termination codons, one base pair insertion, one base pair deletion, and several missense mutations, were also found. Further analysis of these mutations may provide insight into the importance of various structural motifs to the function of this transport protein.

Taken together, these studies definitively establish that the SPGP is the major bile salt excretory pump of mammalian liver. It is also clear that mutations in SPGP, which are predicted to disrupt gene function, have been identified in a major subtype of PFIC. The disease in these patients caused by inactivating mutations of the human bile salt excretory pump is compatible with a loss of the ability to efficiently excrete bile acids into the bile canaliculus and a marked reduction in bile acid dependent bile flow. Bile acids retained within hepatocytes cause progressive injury and, with efflux of bile salts back into the blood, a progressive increase in serum bile acid concentrations. The low biliary bile acid concentrations seen in patients with PFIC2 may be insufficient to release ␥ GT from biliary epithelium, with the result that serum ␥ GT levels remain paradoxically normal in these severely cholestatic patients.