title: Znf202 affects high density lipoprotein cholesterol levels and promotes hepatosteatosis in hyperlipidemic mice.
abstract: BACKGROUND
  The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established.
  
  
  RESULTS
  We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression.
  
  
  CONCLUSIONS
  Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands. c_vrins@hotmail.com
authors.forename: Carlos L J
authors.initials: CL
authors.lastname: Vrins
authors.forename: Ruud
authors.initials: R
authors.lastname: Out
authors.forename: Peter
authors.initials: P
authors.lastname: van Santbrink
authors.forename: André
authors.initials: A
authors.lastname: van der Zee
authors.forename: Tokameh
authors.initials: T
authors.lastname: Mahmoudi
authors.forename: Martine
authors.initials: M
authors.lastname: Groenendijk
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Ko
authors.initials: K
authors.lastname: Willems van Dijk
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D008076:Cholesterol, HDL / Q000097:blood*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005234:Fatty Liver / Q000097:blood / Q000150:complications*; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D008076:Cholesterol, HDL; D017931:DNA Primers; D012097:Repressor Proteins; C583311:Znf202 protein, mouse