Rapamycin inhibits postprandial-mediated X-box-binding protein-1 splicing in rat liver.
Recent studies have linked the unfolded protein response (UPR), in particular the inositol-requiring, endoplasmic reticulum-to-nucleus signaling protein 1alpha (IRE1alpha)-X-box-binding protein-1 (XBP1) branch of the UPR, to the regulation of lipogenesis and hepatic steatosis. In this study, we examined the hypothesis that the postprandial environment can activate the IRE1alpha-XBP1 branch of the UPR in the liver via a mammalian target of rapamycin complex 1 (mTORC1)-dependent mechanism. Toward this end, rats were fed a high-carbohydrate diet (68% of energy from corn starch) for 3 h in the absence or presence of rapamycin (intraperitoneal injection of 1 mg/kg) and liver tissue was taken 1 or 7 h following the feeding period. Feeding activated the mTORC1 pathway and IRE1alpha, induced XBP1 splicing, and increased the expression of XBP1 target genes and lipogenic genes in the liver. The presence of rapamycin prevented the activation of mTORC1 and IRE1alpha, XBP1 splicing, and the increased expression of XBP1 target genes and lipogenic genes. Rapamycin also prevented the feeding-induced increase in nuclear sterol regulatory element binding protein 1c. These data suggest that the postprandial environment promotes activation of the IRE1-XBP1 branch of the UPR in the liver. This activation appears to be mediated in part by mTORC1.
Pfaffenbach
Kyle T
KT
Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA.
Nivala
Angela M
AM
Reese
Lauren
L
Ellis
Flannery
F
Wang
Dong
D
Wei
Yuren
Y
Pagliassotti
Michael J
MJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004040:Dietary Carbohydrates; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D019518:Postprandial Period; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000071701:Regulatory Factor X Transcription Factors; D020123:Sirolimus / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D004040:Dietary Carbohydrates; D047908:Intracellular Signaling Peptides and Proteins; D000071701:Regulatory Factor X Transcription Factors; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605545:Xbp1 protein, rat; C546842:MTOR protein, human; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus