The E2F2 transcription factor sustains hepatic glycerophospholipid homeostasis in mice.
Increasing evidence links metabolic signals to cell proliferation, but the molecular wiring that connects the two core machineries remains largely unknown. E2Fs are master regulators of cellular proliferation. We have recently shown that E2F2 activity facilitates the completion of liver regeneration after partial hepatectomy (PH) by regulating the expression of genes required for S-phase entry. Our study also revealed that E2F2 determines the duration of hepatectomy-induced hepatic steatosis. A transcriptomic analysis of normal adult liver identified "lipid metabolism regulation" as a major E2F2 functional target, suggesting that E2F2 has a role in lipid homeostasis. Here we use wild-type (E2F2+/+) and E2F2 deficient (E2F2-/-) mice to investigate the in vivo role of E2F2 in the composition of liver lipids and fatty acids in two metabolically different contexts: quiescence and 48-h post-PH, when cellular proliferation and anabolic demands are maximal. We show that liver regeneration is accompanied by large triglyceride and protein increases without changes in total phospholipids both in E2F2+/+ and E2F2-/- mice. Remarkably, we found that the phenotype of quiescent liver tissue from E2F2-/- mice resembles the phenotype of proliferating E2F2+/+ liver tissue, characterized by a decreased phosphatidylcholine to phosphatidylethanolamine ratio and a reprogramming of genes involved in generation of choline and ethanolamine derivatives. The diversity of fatty acids in total lipid, triglycerides and phospholipids was essentially preserved on E2F2 loss both in proliferating and non-proliferating liver tissue, although notable exceptions in inflammation-related fatty acids of defined phospholipid classes were detected. Overall, our results indicate that E2F2 activity sustains the hepatic homeostasis of major membrane glycerolipid components while it is dispensable for storage glycerolipid balance.
Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain; Instituto de Investigaciones Bioquímicas de Bahía Blanca, Consejo Nacional de Investigaciones Científicas y Técnicas y Universidad Nacional del Sur, Bahía Blanca, Argentina.
Eduardo N
EN
Maldonado
Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.
Igotz
I
Delgado
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Consejo Nacional de Investigaciones Científicas y Técnicas y Universidad Nacional del Sur, Bahía Blanca, Argentina.
Natalia E
NE
Furland
Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.
Xabier
X
Buqué
Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country, Leioa, Spain.
Ainhoa
A
Iglesias
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Consejo Nacional de Investigaciones Científicas y Técnicas y Universidad Nacional del Sur, Bahía Blanca, Argentina.
Marta I
MI
Aveldaño
Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country, Leioa, Spain.
Ana
A
Zubiaga
Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.
Olatz
O
Fresnedo
Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.
Begoña
B
Ochoa
D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D020404:Glycerophospholipids / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
D050703:E2F2 Transcription Factor; C484940:E2f2 protein, mouse; D005227:Fatty Acids; D020404:Glycerophospholipids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011506:Proteins; D014280:Triglycerides; C483858:phosphatidylethanolamine