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Membrane monocarboxylate transporter 1 (SLC16A1/MCT1) plays an important role in
hepatocyte homeostasis, as well as drug handling. However, there is no available information
about the impact of liver pathology on the transporter levels and function. The study was aimed to
quantify SLC16A1 mRNA (qRT-PCR) and MCT1 protein abundance (liquid chromatography–tandem
mass spectrometry (LC¬¬–MS/MS)) in the livers of patients diagnosed, according to the standard
clinical criteria, with hepatitis C, primary biliary cirrhosis, primary sclerosing hepatitis, alcoholic liver
disease (ALD), and autoimmune hepatitis. The stage of liver dysfunction was classified according to
Child–Pugh score. Downregulation of SLC16A1/MCT1 levels was observed in all liver pathology
states, significantly for ALD. The progression of liver dysfunction, from Child–Pugh class A to C,
involved the gradual decline in SLC16A1 mRNA and MCT1 protein abundance, reaching a clinically
significant decrease in class C livers. Reduced levels of MCT1 were associated with significant
intracellular lactate accumulation. The MCT1 transcript and protein did not demonstrate significant
correlations regardless of the liver pathology analyzed, as well as the disease stage, suggesting
posttranscriptional regulation, and several microRNAs were found as potential regulators of MCT1
abundance. MCT1 membrane immunolocalization without cytoplasmic retention was observed in all
studied liver pathologies. Overall, the study demonstrates that SLC16A1/MCT1 is involved in liver
pathology, especially in ALD
Liver diseases are important causes of morbidity and mortality worldwide. The aim of
this study was to identify differentially expressed microRNAs (miRNAs), target genes, and key
pathways as innovative diagnostic biomarkers in liver patients with different pathology and functional
state. We determined, using RT-qPCR, the expression of 472 miRNAs in 125 explanted livers from
subjects with six different liver pathologies and from control livers. ANOVA was employed to
obtain differentially expressed miRNAs (DEMs), and miRDB (MicroRNA target prediction database)
was used to predict target genes. A miRNA–gene differential regulatory (MGDR) network was
constructed for each condition. Key miRNAs were detected using topological analysis. Enrichment
analysis for DEMs was performed using the Database for Annotation, Visualization, and Integrated
Discovery (DAVID). We identified important DEMs common and specific to the different patient
groups and disease progression stages. hsa-miR-1275 was universally downregulated regardless
the disease etiology and stage, while hsa-let-7a*, hsa-miR-195, hsa-miR-374, and hsa-miR-378 were
deregulated. The most significantly enriched pathways of target genes controlled by these miRNAs
comprise p53 tumor suppressor protein (TP53)-regulated metabolic genes, and those involved in
regulation of methyl-CpG-binding protein 2 (MECP2) expression, phosphatase and tensin homolog
(PTEN) messenger RNA (mRNA) translation and copper homeostasis. Our findings show a novel
panel of deregulated miRNAs in the liver tissue from patients with different liver pathologies. These
miRNAs hold potential as biomarkers for diagnosis and staging of liver diseases.
Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology
(2021)
Transmembrane drug transport in hepatocytes is one of the major determinants of drug pharmacokinetics. In the present study, ABC transporters (P-gp, MRP1, MRP2, MRP3, MRP4, BCRP, and BSEP) and SLC transporters (MCT1, NTCP, OAT2, OATP1B1, OATP1B3, OATP2B1, OCT1, and OCT3) were quantified for protein abundance (LC-MS/MS) and mRNA levels (qRT-PCR) in hepatitis C virus (HCV)-infected liver samples from the Child–Pugh class A (n = 30), B (n = 21), and C (n = 7) patients. Protein levels of BSEP, MRP3, MCT1, OAT2, OATP1B3, and OCT3 were not significantly affected by HCV infection. P-gp, MRP1, BCRP, and OATP1B3 protein abundances were upregulated, whereas those of MRP2, MRP4, NTCP, OATP2B1, and OCT1 were downregulated in all HCV samples. The observed changes started to be seen in the Child–Pugh class A livers, i.e., upregulation of P-gp and MRP1 and downregulation of MRP2, MRP4, BCRP, and OATP1B3. In the case of NTCP, OATP2B1, and OCT1, a decrease in the protein levels was observed in the class B livers. In the class C livers, no other changes were noted than those in the class A and B patients. The results of the study demonstrate that drug transporter protein abundances are affected by the functional state of the liver in hepatitis C patients.