Induction of hepatic ABC transporter expression is part of the PPARalpha-mediated fasting response in the mouse.
OBJECTIVE
Fatty acids are natural ligands of the peroxisome proliferator-activated receptor alpha (PPARalpha). Synthetic ligands of this nuclear receptor, i.e., fibrates, induce the hepatic expression of the multidrug resistance 2 gene (Mdr2), encoding the canalicular phospholipid translocator, and affect hepatobiliary lipid transport. We tested whether fasting-associated fatty acid release from adipose tissues alters hepatic transporter expression and bile formation in a PPARalpha-dependent manner.


METHODS
A 24-hour fasting/48-hour refeeding schedule was used in wild-type and Pparalpha((-/-)) mice. Expression of genes involved in the control of bile formation was determined and related to secretion rates of biliary components.


RESULTS
Expression of Pparalpha, farnesoid X receptor, and liver X receptor alpha genes encoding nuclear receptors that control hepatic bile salt and sterol metabolism was induced on fasting in wild-type mice only. The expression of Mdr2 was 5-fold increased in fasted wild-type mice and increased only marginally in Pparalpha((-/-)) mice, and it normalized on refeeding. Mdr2 protein levels and maximal biliary phospholipid secretion rates were clearly increased in fasted wild-type mice. Hepatic expression of the liver X receptor target genes ATP binding cassette transporter a1 (Abca1), Abcg5, and Abcg8, implicated in hepatobiliary cholesterol transport, was induced in fasted wild-type mice only. However, the maximal biliary cholesterol secretion rate was reduced by approximately 50%.


CONCLUSIONS
Induction of Mdr2 expression and function is part of the PPARalpha-mediated fasting response in mice. Fasting also induces expression of the putative hepatobiliary cholesterol transport genes Abca1, Abcg5, and Abcg8, but, nonetheless, maximal biliary cholesterol excretion is decreased after fasting.
Kok
Tineke
T
Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, CMC IV, Room Y2.163, Groningen University Institute for Drug Exploration, Academic Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. T.Kok@med.rug.nl
Wolters
Henk
H
Bloks
Vincent W
VW
Havinga
Rick
R
Jansen
Peter L M
PL
Staels
Bart
B
Kuipers
Folkert
F
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000821:Animal Feed; D000818:Animals; D001646:Bile / Q000502:physiology; D005215:Fasting / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D012016:Reference Values; D014157:Transcription Factors / Q000502:physiology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C095122:multidrug resistance protein 3