title: Impaired liver regeneration in Ldlr-/- mice is associated with an altered hepatic profile of cytokines, growth factors, and lipids.
abstract: OBJECTIVE
  It is widely recognized that in the early stages of liver regeneration after partial hepatectomy, the hepatocytes accumulate a significant amount of lipids. The functional meaning of this transient steatosis and its effect on hepatocellular proliferation are not well defined. In addition, the basic mechanisms of this lipid accumulation are not well understood although some studies suggest the participation of the Low Density Lipoprotein Receptor (Ldlr).
  
  
  METHODS
  To address these questions, we studied the process of liver regeneration in Ldlr null mice and wild type mice following partial hepatectomy.
  
  
  RESULTS
  Ldlr deficiency was associated with a significant decrease in serum albumin concentration, during early stages of liver regeneration, and a delayed hepatic regeneration. Remnant livers of Ldlr(-)(/)(-) showed a time-shifted expression of interleukin-6 (IL6) and a defective activation of tumor necrosis factor-α (TNFα) and hepatocyte growth factor (HGF) expression in early phases of liver regeneration. Unexpectedly, Ldlr(-)(/)(-) showed no significant differences in the content of lipid droplets after partial hepatectomy compared to wild type mice. However, lipidomic analysis of the regenerating liver from Ldlr(-)(/)(-) revealed a lipid profile compatible with liver quiescence: high content of cholesterol esters and ceramide, and low levels of phosphatidylcholine.
  
  
  CONCLUSIONS
  Ldlr deficiency is associated with significant changes in the hepatic lipidome that affect cytokine-growth factor signaling and impair liver regeneration. These results suggest that the analysis of the hepatic lipidome may help predict the success of liver regeneration in the clinical environment, specifically in the context of pre-existing liver steatosis.
authors.affiliation: Centro Esther Koplowitz, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Pauta
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.forename: Frances
authors.initials: F
authors.lastname: Vales
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Hernando
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Allen
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.forename: Montserrat
authors.initials: M
authors.lastname: Marí
authors.forename: Wladimiro
authors.initials: W
authors.lastname: Jiménez
authors.forename: Angel
authors.initials: A
authors.lastname: Baldán
authors.forename: Manuel
authors.initials: M
authors.lastname: Morales-Ruiz
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006498:Hepatectomy / Q000009:adverse effects; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C553307:HGF protein, mouse; D015850:Interleukin-6; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D002784:Cholesterol
keywords: Lipidomics; Liver regeneration; Low-density lipoprotein receptor; Partial hepatectomy; Steatosis