Abstract
BackgroundThe 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 FindingsWe 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/SignificanceZnf202 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.
Highlights
Hypoalphalipoproteinemia is characterized by subnormal levels of serum high density lipoprotein (HDL) irrespective of other lipoprotein or lipid levels
The zinc finger protein 202 (Znf202) gene has been identified in the chromosomal region 11q23 that is linked to heritable hypoalphalipoproteinemia in Utah pedigrees and distinct from an apolipoprotein gene cluster ApoAI/CIII/AIV/AV [11,12]
We analyzed the effect of Znf202 overexpression on the Apoe/c1/c2 and Apoa1/c3/a4/a5 gene clusters in mhAT3F2 cells
Summary
Hypoalphalipoproteinemia is characterized by subnormal levels of serum high density lipoprotein (HDL) irrespective of other lipoprotein or lipid levels It is a common lipoprotein abnormality in patients with coronary heart disease and low HDL levels were shown in various studies to be linked to risk factors like diabetes and hyperlipidemia [1,2]. The specific function of these domains is still under investigation, the presence of a KRAB domain in Znf202 is suggestive of transcriptional repressor activity [17] This is corroborated by in vitro findings showing repressional activity of Znf202 on a range of target genes involved in lipid metabolism including ATP-binding cassette (ABC) transporters Abca, Abcg and apolipoproteins Apoe and Apoa, in hepatoma cells [12] as well as monocytes [18]. A functional role of Znf202 in lipid metabolism in vivo still remains to be established
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