The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia

Gustavo W. Fernandes; Barbara M.L.C. Bocco; Tatiana L. Fonseca; Elizabeth A. McAninch; Sungro Jo; Lattoya J. Lartey; In Sug O-Sullivan; Terry G. Unterman; Nailliw Z. Preite; Robin M. Voigt; Christopher B. Forsyth; Ali Keshavarzian; Richárd Sinkó; Allison B. Goldfine; Mary E. Patti; Miriam O. Ribeiro; Balázs Gereben; Antonio C. Bianco

doi:10.1016/j.celrep.2017.12.053

The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia

Gustavo W. Fernandes, Barbara M.L.C. Bocco, Tatiana L. Fonseca, Elizabeth A. McAninch, Sungro Jo, Lattoya J. Lartey, In Sug O-Sullivan, Terry G. Unterman, Nailliw Z. Preite, Robin M. Voigt, Christopher B. Forsyth, Ali Keshavarzian, Richárd Sinkó, Allison B. Goldfine, Mary E. Patti, Miriam O. Ribeiro, Balázs Gereben, Antonio C. Bianco

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an “Alb-D2KO-like” metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia. Mice with liver-specific disruption of the type 2 deiodinase gene are resistant to both diet-induced obesity and hepatosteatosis. Fernandes et al. show that this is due to a reduction in liver expression of zinc-finger protein-125, a Foxo1-inducible transcriptional repressor that causes lipid accumulation by reducing hepatic secretion of VLDL.

Original language	English (US)
Pages (from-to)	523-534
Number of pages	12
Journal	Cell Reports
Volume	22
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2017.12.053
State	Published - 2018
Externally published	Yes

Keywords

cholesterol
deiodinase
hepatocytes
liver
steatosis
transcriptional repressor
triglycerides
zinc finger protein 125

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2017.12.053

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Fernandes, G. W., Bocco, B. M. L. C., Fonseca, T. L., McAninch, E. A., Jo, S., Lartey, L. J., O-Sullivan, I. S., Unterman, T. G., Preite, N. Z., Voigt, R. M., Forsyth, C. B., Keshavarzian, A., Sinkó, R., Goldfine, A. B., Patti, M. E., Ribeiro, M. O., Gereben, B., & Bianco, A. C. (2018). The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia. Cell Reports, 22(2), 523-534. https://doi.org/10.1016/j.celrep.2017.12.053

Fernandes, GW, Bocco, BMLC, Fonseca, TL, McAninch, EA, Jo, S, Lartey, LJ, O-Sullivan, IS, Unterman, TG, Preite, NZ, Voigt, RM, Forsyth, CB, Keshavarzian, A, Sinkó, R, Goldfine, AB, Patti, ME, Ribeiro, MO, Gereben, B & Bianco, AC 2018, 'The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia', Cell Reports, vol. 22, no. 2, pp. 523-534. https://doi.org/10.1016/j.celrep.2017.12.053

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title = "The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia",

abstract = "Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an “Alb-D2KO-like” metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia. Mice with liver-specific disruption of the type 2 deiodinase gene are resistant to both diet-induced obesity and hepatosteatosis. Fernandes et al. show that this is due to a reduction in liver expression of zinc-finger protein-125, a Foxo1-inducible transcriptional repressor that causes lipid accumulation by reducing hepatic secretion of VLDL.",

keywords = "cholesterol, deiodinase, hepatocytes, liver, steatosis, transcriptional repressor, triglycerides, zinc finger protein 125",

author = "Fernandes, {Gustavo W.} and Bocco, {Barbara M.L.C.} and Fonseca, {Tatiana L.} and McAninch, {Elizabeth A.} and Sungro Jo and Lartey, {Lattoya J.} and O-Sullivan, {In Sug} and Unterman, {Terry G.} and Preite, {Nailliw Z.} and Voigt, {Robin M.} and Forsyth, {Christopher B.} and Ali Keshavarzian and Rich{\'a}rd Sink{\'o} and Goldfine, {Allison B.} and Patti, {Mary E.} and Ribeiro, {Miriam O.} and Bal{\'a}zs Gereben and Bianco, {Antonio C.}",

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year = "2018",

doi = "10.1016/j.celrep.2017.12.053",

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AU - Fernandes, Gustavo W.

AU - Bocco, Barbara M.L.C.

AU - Fonseca, Tatiana L.

AU - McAninch, Elizabeth A.

AU - Jo, Sungro

AU - Lartey, Lattoya J.

AU - O-Sullivan, In Sug

AU - Unterman, Terry G.

AU - Preite, Nailliw Z.

AU - Voigt, Robin M.

AU - Forsyth, Christopher B.

AU - Keshavarzian, Ali

AU - Sinkó, Richárd

AU - Goldfine, Allison B.

AU - Patti, Mary E.

AU - Ribeiro, Miriam O.

AU - Gereben, Balázs

AU - Bianco, Antonio C.

PY - 2018

Y1 - 2018

N2 - Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an “Alb-D2KO-like” metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia. Mice with liver-specific disruption of the type 2 deiodinase gene are resistant to both diet-induced obesity and hepatosteatosis. Fernandes et al. show that this is due to a reduction in liver expression of zinc-finger protein-125, a Foxo1-inducible transcriptional repressor that causes lipid accumulation by reducing hepatic secretion of VLDL.

AB - Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an “Alb-D2KO-like” metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia. Mice with liver-specific disruption of the type 2 deiodinase gene are resistant to both diet-induced obesity and hepatosteatosis. Fernandes et al. show that this is due to a reduction in liver expression of zinc-finger protein-125, a Foxo1-inducible transcriptional repressor that causes lipid accumulation by reducing hepatic secretion of VLDL.

KW - cholesterol

KW - deiodinase

KW - hepatocytes

KW - liver

KW - steatosis

KW - transcriptional repressor

KW - triglycerides

KW - zinc finger protein 125

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ER -

The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia

Abstract

Keywords

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