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Znf202 affects high density lipoprotein cholesterol levels and promotes hepatosteatosis in hyperlipidemic mice.

Vrins CL, Out R, van Santbrink P, van der Zee A, Mahmoudi T, Groenendijk M, Havekes LM, van Berkel TJ, Willems van Dijk K, Biessen EA - PLoS ONE (2013)

Bottom Line: The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified.Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands. c_vrins@hotmail.com

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.

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Related in: MedlinePlus

Hepatic Znf202 overexpression reduces HDL-cholesterol in Ldlr−/− and WT mice.Blood samples were drawn from Ldlr−/− (n = 4; left panels) and WT mice (n = 4; right panels) 5 days after injection with 2.109 pfu of Ad.Znf202 (filled bars) or with Ad-mock (open bars) and derived plasma was analyzed for triglyceride and total cholesterol content (A). Lipoprotein profiles were determined from Ldlr−/− (left panels) and WT mice (right panels) 5 days after injection with Ad.Znf202 (triangles) or with Ad-Mock (squares). The elution fractions were tested for triglyceride and total cholesterol content (B). * and ** indicates p<0.05 and p<0.001, respectively.
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pone-0057492-g003: Hepatic Znf202 overexpression reduces HDL-cholesterol in Ldlr−/− and WT mice.Blood samples were drawn from Ldlr−/− (n = 4; left panels) and WT mice (n = 4; right panels) 5 days after injection with 2.109 pfu of Ad.Znf202 (filled bars) or with Ad-mock (open bars) and derived plasma was analyzed for triglyceride and total cholesterol content (A). Lipoprotein profiles were determined from Ldlr−/− (left panels) and WT mice (right panels) 5 days after injection with Ad.Znf202 (triangles) or with Ad-Mock (squares). The elution fractions were tested for triglyceride and total cholesterol content (B). * and ** indicates p<0.05 and p<0.001, respectively.

Mentions: Plasma total cholesterol (TC) levels were 2-fold increased in Ad.Znf202 treated Ldlr−/− mice on day 5 after gene transfer (P<0.001), whereas in WT mice Znf202 overexpression had a slight lowering effect on plasma TC levels (Fig. 3A). Surprisingly, triglyceride (TG) levels were reduced by 4-fold (P<0.05) in Ldlr−/− mice only. The elevated plasma TC levels in Ldlr−/− mice overexpressing Znf202 appeared to be attributable to an increased cholesterol content of the VLDL pool (Fig. 3B). In keeping with its presumed role in hypoalphalipoproteinemia, Znf202 overexpression led to a marked reduction in HDL-cholesterol both in WT and in Ldlr−/− mice (−63% and −70% respectively).


Znf202 affects high density lipoprotein cholesterol levels and promotes hepatosteatosis in hyperlipidemic mice.

Vrins CL, Out R, van Santbrink P, van der Zee A, Mahmoudi T, Groenendijk M, Havekes LM, van Berkel TJ, Willems van Dijk K, Biessen EA - PLoS ONE (2013)

Hepatic Znf202 overexpression reduces HDL-cholesterol in Ldlr−/− and WT mice.Blood samples were drawn from Ldlr−/− (n = 4; left panels) and WT mice (n = 4; right panels) 5 days after injection with 2.109 pfu of Ad.Znf202 (filled bars) or with Ad-mock (open bars) and derived plasma was analyzed for triglyceride and total cholesterol content (A). Lipoprotein profiles were determined from Ldlr−/− (left panels) and WT mice (right panels) 5 days after injection with Ad.Znf202 (triangles) or with Ad-Mock (squares). The elution fractions were tested for triglyceride and total cholesterol content (B). * and ** indicates p<0.05 and p<0.001, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585336&req=5

pone-0057492-g003: Hepatic Znf202 overexpression reduces HDL-cholesterol in Ldlr−/− and WT mice.Blood samples were drawn from Ldlr−/− (n = 4; left panels) and WT mice (n = 4; right panels) 5 days after injection with 2.109 pfu of Ad.Znf202 (filled bars) or with Ad-mock (open bars) and derived plasma was analyzed for triglyceride and total cholesterol content (A). Lipoprotein profiles were determined from Ldlr−/− (left panels) and WT mice (right panels) 5 days after injection with Ad.Znf202 (triangles) or with Ad-Mock (squares). The elution fractions were tested for triglyceride and total cholesterol content (B). * and ** indicates p<0.05 and p<0.001, respectively.
Mentions: Plasma total cholesterol (TC) levels were 2-fold increased in Ad.Znf202 treated Ldlr−/− mice on day 5 after gene transfer (P<0.001), whereas in WT mice Znf202 overexpression had a slight lowering effect on plasma TC levels (Fig. 3A). Surprisingly, triglyceride (TG) levels were reduced by 4-fold (P<0.05) in Ldlr−/− mice only. The elevated plasma TC levels in Ldlr−/− mice overexpressing Znf202 appeared to be attributable to an increased cholesterol content of the VLDL pool (Fig. 3B). In keeping with its presumed role in hypoalphalipoproteinemia, Znf202 overexpression led to a marked reduction in HDL-cholesterol both in WT and in Ldlr−/− mice (−63% and −70% respectively).

Bottom Line: The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified.Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands. c_vrins@hotmail.com

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.

Show MeSH
Related in: MedlinePlus