Title
Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice
Author
Vrins, C.L.J.
Out, R.
van Santbrink, P.
van der Zee, A.
Mahmoudi, T.
Groenendijk, M.
Havekes, L.M.
van Berkel, T.J.C.
van Dijk, K.W.
Biessen, E.A.L.
Publication year
2013
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. Methodology and Principal Findings: 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. Conclusion/Significance: 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. © 2013 Vrins et al.
Subject
EELS - Earth, Environmental and Life Sciences
Life
Healthy Living
Biomedical Innovation
MHR - Metabolic Health Research
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http://resolver.tudelft.nl/uuid:7ae68fc3-ba8a-4f93-9737-dbf9d6a3f124
DOI
https://doi.org/10.1371/journal.pone.0057492
TNO identifier
470336
ISSN
1932-6203
Source
PLoS ONE, 8 (8)
Document type
article