title: PPAR-beta facilitating maturation of hepatic-like tissue derived from mouse embryonic stem cells accompanied by mitochondriogenesis and membrane potential retention.
abstract: Relatively little is known about mitochondria metabolism in differentiating embryonic stem (ES) cells. Present research focused on several elements of cellular energy metabolism in hepatic-like tissue derived from mouse ES cells. We demonstrated that mitochondrial location patterns and mitochondrial membrane potential (DeltaPsi(m)) existed in subsequent differentiation of the tissue. Mitochondriogenesis appeared at the early stage and kept a normal DeltaPsi(m) in differentiated mature hepatocytes. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) expression was transitorily increased at the beginning, and kept a relatively low level later, which accompanied by expression of PPAR-gamma coactivator (PGC)-1alpha, a master regulator of mitochondrial biogenesis. PPAR-beta expression showed robust up-regulation in the late differentiation course. Enhanced co-expressions of PPAR-beta and albumin with catalysis of UDP-glucuronosyltransferases (UGTs) were observed at mature stage. While PPAR-gamma expression changed little before and after differentiation. Mitochondriogenesis could be accelerated by PPAR-alpha specific agonist WY14643 and abolished by its antagonist GW6471 at the early stage. Neither of them affected mitochondrial DeltaPsi(m) and albumin generation in the differentiated hepatocytes. Furthermore, maturation of hepatic-like tissue and mitochondriogenesis in hepatocyte could be efficiently stimulated by PPAR-beta specific agonist L165041 and abolished by PPAR-beta specific antagonist GSK0660, but not affected by PPAR-gamma specific agonist GW1929. In conclusion, the derived hepatic tissue morphologically possessed cellular energy metabolism features. PPAR-alpha seemed only necessary for early mitochondriogenesis, while less important for DeltaPsi(m) retention in the mature tissue derived. The stimulation of PPAR-beta but not -gamma enhanced hepatogenesis, hepatocytes maturation, and mitochondriogenesis. PPAR-beta took an important role in cellular energy metabolism of hepatogenesis.
authors.affiliation: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou 310058, China. zdyzxb@zju.edu.cn
authors.forename: Dan-Yan
authors.initials: DY
authors.lastname: Zhu
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Wu
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.forename: Jie-Ping
authors.initials: JP
authors.lastname: Yan
authors.forename: Mei-Yuan
authors.initials: MY
authors.lastname: Guo
authors.forename: Yan-Bo
authors.initials: YB
authors.lastname: Wo
authors.forename: Yi-Jia
authors.initials: YJ
authors.lastname: Lou
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D038081:Organogenesis / Q000502:physiology; D048068:PPAR-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048068:PPAR-beta