title: Retinol binding protein 4 stimulates hepatic sterol regulatory element-binding protein 1 and increases lipogenesis through the peroxisome proliferator-activated receptor-γ coactivator 1β-dependent pathway.
abstract: Recent studies have revealed the essential role of retinol binding protein 4 (RBP4) in insulin resistance. However, the impact of RBP4 on aberrant lipogenesis, the common hepatic manifestation in insulin resistance states, and the underlying mechanism remain elusive. The present study was designed to examine the effect of RBP4 on sterol regulatory element-binding protein (SREBP-1) and hepatic lipogenesis. Treatment with human retinol-bound RBP4 (holo-RBP4) significantly induced intracellular triglyceride (TAG) synthesis in HepG2 cells and this effect is retinol-independent. Furthermore, RBP4 treatment enhanced the levels of mature SREBP-1 and its nuclear translocation, thereby increasing the expression of lipogenic genes, including fatty acid synthase (FAS), acetyl coenzyme A carboxylase-1 (ACC-1), and diacylglycerol O-acyltransferase 2 (DGAT-2). Stimulation of HepG2 cells with RBP4 strongly up-regulated the expression of transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) at both the messenger RNA (mRNA) and protein levels. The transcriptional activation of PGC-1β is necessary and sufficient for the transcriptional activation of SREBP-1 in response to RBP4. The cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) was identified as the target transcription factor involved in the RBP4-mediated up-regulation of PGC-1β transcription as a result of phosphorylation on Ser133. Furthermore, in vivo RBP4 infusion induced SREBP-1c activation and consequently accelerated hepatic lipogenesis and plasma TAG in C57BL/6J mice, a phenomenon not observed in Ppargc1b knockout mice.
  
  
  CONCLUSIONS
  These findings reveal a novel mechanism by which RBP4 achieves its effects on hepatic lipid metabolism.
authors.affiliation: Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong Province, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Honghui
authors.initials: H
authors.lastname: Guo
authors.forename: Duan
authors.initials: D
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenhua
authors.initials: W
authors.lastname: Ling
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054839:Retinol-Binding Proteins, Plasma / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors