A novel pregnane X receptor and S14-mediated lipogenic pathway in human hepatocyte.
The pregnane X receptor (PXR) initially isolated as a nuclear receptor regulating xenobiotic and drug metabolism and elimination, seems to play an endobiotic role by affecting lipid homeostasis. In mice, PXR affects lipid homeostasis and increases hepatic deposit of triglycerides. In this study, we show that, in human hepatocyte, PXR activation induces an increase of de novo lipogenesis through the up-regulation of S14. S14 was first identified as a thyroid-responsive gene and is known to transduce hormone-related and nutrient-related signals to genes involved in lipogenesis through a molecular mechanism not yet elucidated. We demonstrate that S14 is a novel transcriptional target of PXR. In addition, we report an increase of fatty acid synthase (FASN) and adenosine triphosphate citrate lyase genes expression after PXR activation in human hepatocyte, leading to an increase of fatty acids accumulation and de novo lipogenesis. RNA interference of the expression of S14 proportionally decreases the FASN induction, whereas S14 overexpression in human hepatic cells provokes an increase of fatty acids accumulation and lipogenesis. These results demonstrate for the first time that xenobiotic or drug-activated PXR promote aberrant hepatic de novo lipogenesis via activation of the nonclassical S14 pathway. In addition, these data suggest that the up-regulation of S14 by PXR may promote aberrant hepatic lipogenesis and hepatic steatosis in human hepatocytes.
Institut National de la Santé et de la Recherche Médicale, U632, Montpellier, F-34293 France.
Amélie
A
Moreau
Christelle
C
Téruel
Michel
M
Beylot
Valérie
V
Albalea
Viola
V
Tamasi
Thierry
T
Umbdenstock
Yannick
Y
Parmentier
Antonio
A
Sa-Cunha
Bertrand
B
Suc
Jean-Michel
JM
Fabre
Francis
F
Navarro
Jeanne
J
Ramos
Urs
U
Meyer
Patrick
P
Maurel
Marie-José
MJ
Vilarem
Jean-Marc
JM
Pascussi
D000818:Animals; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D009687:Nuclear Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C501477:Thrsp protein, mouse; D014157:Transcription Factors