title: Impaired cell proliferation in regenerating liver of 3 β-hydroxysterol Δ14-reductase (TM7SF2) knock-out mice.
abstract: The liver is the most important organ in cholesterol metabolism, which is instrumental in regulating cell proliferation and differentiation. The gene Tm7sf2 codifies for 3 β-hydroxysterol-Δ14-reductase (C14-SR), an endoplasmic reticulum resident protein catalyzing the reduction of C14-unsaturated sterols during cholesterol biosynthesis from lanosterol. In this study we analyzed the role of C14-SR in vivo during cell proliferation by evaluating liver regeneration in Tm7sf2 knockout (KO) and wild-type (WT) mice. Tm7sf2 KO mice showed no alteration in cholesterol content. However, accumulation and delayed catabolism of hepatic triglycerides was observed, resulting in persistent steatosis at all times post hepatectomy. Moreover, delayed cell cycle progression to the G1/S phase was observed in Tm7sf2 KO mice, resulting in reduced cell division at the time points examined. This was associated to abnormal ER stress response, leading to alteration in p53 content and, consequently, induction of p21 expression in Tm7sf2 KO mice. In conclusion, our results indicate that Tm7sf2 deficiency during liver regeneration alters lipid metabolism and generates a stress condition, which, in turn, transiently unbalances hepatocytes cell cycle progression.
authors.affiliation: a Department of Experimental Medicine , University of Perugia , Perugia , Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bartoli
authors.affiliation: a Department of Experimental Medicine , University of Perugia , Perugia , Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Piobbico
authors.affiliation: a Department of Experimental Medicine , University of Perugia , Perugia , Italy.
authors.forename: Marina Maria
authors.initials: MM
authors.lastname: Bellet
authors.affiliation: a Department of Experimental Medicine , University of Perugia , Perugia , Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Bennati
authors.affiliation: a Department of Experimental Medicine , University of Perugia , Perugia , Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Roberti
authors.affiliation: a Department of Experimental Medicine , University of Perugia , Perugia , Italy.
authors.forename: Maria Agnese
authors.initials: MA
authors.lastname: Della Fazia
authors.affiliation: a Department of Experimental Medicine , University of Perugia , Perugia , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Servillo
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000150:complications; D016193:G1 Phase; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000032:analysis; D008115:Liver Regeneration / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D000097682:Lamin B Receptor
chemical_list: D008055:Lipids; D010088:Oxidoreductases; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor; C022672:delta(14)-sterol reductase
keywords: 3β-Hydroxysterol Δ14-Reductase; ER stress; cell cycle; cell proliferation; liver regeneration; p53; partial hepatectomy