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

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.The study design, data collection and analysis and decision to publish were funded by the Department of Education, Universities and Research of the Basque Goverment (grants IT336/10 to BO and OF and IT634/2013 to AZ) and the Department of Industry of the Basque Government(grants PE13UN139 to BO and IE12-331 to AZ). The preparation of the manuscript and the publication costs were funded by the University of the Basque Country (grant UFI11/20 to AZ, AI, BO, OF and XB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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.Fil: Maldonado, Eduardo N.. Universidad del Pais Vasco; EspañaFil: Delgado, Igotz. University Of The Basque Country (upv/ehu). Department Of Chemical And Environmental Engineering, Polytechnic School; EspañaFil: Furland, Natalia Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Buqué, Xabier. Universidad del Pais Vasco; EspañaFil: Iglesias, Ainhoa. Universidad del Pais Vasco; EspañaFil: Aveldaño, Marta Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Zubiaga, Ana. Universidad del Pais Vasco; EspañaFil: Fresnedo, Olatz. Universidad del Pais Vasco; EspañaFil: Ocho, Begoña. Universidad del Pais Vasco; Españ

Effects of feed restriction on milk production and metabolism in mid-lactation dairy cows

Availability of glucose precursors and a proper interorgan coordination during the metabolic cascade of adaptations occurring during periods of lower DMI, are the vital importance to achieve a successful transition from late gestation to lactation. The aim of the study was to determine metabolic responses to a short-term period of negative energy balance induced by feed restriction (FR) and the effect of abomasal supplementation of different amino acids (AA) or glucose. Seven multiparous Holstein cows (93 ± 15 DIM) were randomly assigned to 7 treatments in a 7 × 4 incomplete Latin square design. In 6 treatments, daily DMI was restricted to provide 60% of energy requirements during 5 d; the 7th treatment consisted of ad libitum (AL) intake. Feed was provided once daily at 0900 h. Effects of FR (AL vs RC), day, time within day, and interactions were evaluated with ANOVA using the MIXED procedure of SAS. Evaluating the effect of FR, milk yield (P < 0.01), milk protein concentration (P = 0.03) and yield (P < 0.01), and lactose yield (P < 0.01) were lower for RC, whereas milk fat (P < 0.01) and urea N concentrations were higher (P < 0.01). Treatment RC induced lower plasma insulin (P = 0.01) and glucose (P = 0.04) concentrations, with quadratic (P < 0.01 for both) decreasing trends reaching nadir on d 3. Concentration of NEFA was higher (P < 0.01) and increased quadratically (P < 0.01) with its maximum on d 3 during FR. Serum BHBA increased linearly (P = 0.04) for RC (RC x d; P = 0.16) with its peak at d 4. Catabolism of amino acids (AA) increased early during FR as indicated by plasma urea N increasing (P < 0.01) quadratically (P < 0.01), with its peak on d 2 and decreasing afterward. Accounting for all the amino-N circulating in form of urea or eliminated in milk as MUN, the decrease in concentration of all the AA in circulation analyzed here was not sufficient for the amount of urea synthetized. Therefore, it seems probable that body tissue protein was rapidly mobilized, to produce the energy required to support the higher ECM especially through milk fat and lactose. Plasma 3-methylhistidine increased linearly (P < 0.01) denoting protein tissue mobilization of contractile fibers. A group of AA (Glu, Val, Leu, Tyr, Phe, Ser, His, Thr, Asn, Ala, Pro, Met) decreased in a quadratic manner with the nadir at d 2 and 3, while Asp, Trp and Ile decreased linearly. Concentrations of other AA increased (Gln, Gly, Cys) or did not vary (Lys, Arg) during FR. Plasma AA concentrations decreased after feed delivery in both diets, coinciding with the increase of insulin, except for Glu that increased in all treatments and Gln that increased after feeding only during FR. Metabolic adaptations to low insulin during FR seemed to select catabolism of AA as the first energy source before later relying more on fatty acids. Based on responses of plasma AA and insulin to feeding, protein synthesis in tissues likely remained sensitive to insulin within day