Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4alpha and PGC1alpha.
Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4alpha/PGC-1alpha-pathway. Because HNF4alpha has been identified as central regulator of basolateral bile acid transporters and a previous study reports increased basolateral bile acid uptake into the liver during fasting, we hypothesized that HNF4alpha is involved in fasting-induced bile acid uptake via upregulation of basolateral bile acid transporters. In rats, mRNA of Ntcp, Oatp1, and Oatp2 were significantly increased after 48 h of fasting. Protein expression as determined by Western blot showed significant increases for all three transporters 72 h after the onset of fasting. Whereas binding activity of HNF1alpha in electrophoretic mobility shift assays remained unchanged, HNF4alpha binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4alpha and PGC-1alpha. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4alpha, PGC-1alpha, or a combination of both. We conclude that upregulation of the basolateral bile acid transporters Ntcp, Oatp1, and Oatp2 in fasted rats is mediated via the HNF4alpha/PGC-1alpha pathway.
Dietrich
Christoph G
CG
Department of Internal Medicine III, Division of Gastroenterology and Hepatology, University Hospital Aachen, Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Martin
Ina V
IV
Porn
Anne C
AC
Voigt
Sebastian
S
Gartung
Carsten
C
Trautwein
Christian
C
Geier
Andreas
A
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D045744:Cell Line, Tumor; D005215:Fasting / Q000378:metabolism*; D005508:Food Deprivation; D006360:Heat-Shock Proteins / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
D001647:Bile Acids and Salts; C496592:HNF4A protein, human; D006360:Heat-Shock Proteins; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C421102:Slco1a1 protein, rat; C503597:Slco1a4 protein, rat; D027981:Symporters; D014157:Transcription Factors; C071908:sodium-bile acid cotransporter