Hepatic Expression of the Na-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation.

The hepatic Na-taurocholate cotransporting polypeptide NTCP/ is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic /NTCP expression using various omics technologies. /NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and next-generation sequencing were used for genomic analyses. DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in or other genes do not explain expression variability which was validated in livers ( = 50) from The Cancer Genome Atlas. The identified two missense variants did not impair transport function in transfectants. Specific CpG sites in as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation.

PMID: 35806468