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

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

doi:10.1016/j.celrep.2017.12.053

Cited by 22 publications

(38 citation statements)

References 25 publications

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“…Hepatic Zfp125 protein levels are reduced in adult Alb‐D2KO mice, explaining most of the metabolic phenotype observed in these animals (Fernandes et al., ). Here, we saw that Zfp125 protein levels were induced by approximately 50% in the Cre animals switched to EtOH‐containing diet (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…). Furthermore, only in Alb‐D2KO was there an induction of (i) 6 genes that are normally repressed by Zfp125 (i.e., Mttp, Ldlr, Apoc1, Apoe, Apoh, and Azgp1) (Fernandes et al., ) and (ii) 2 genes that are repressed by neonatal Dio2 expression in liver (i.e., Gpat1 and Abcg1) (Fig. B,C ).…”

Section: Discussionmentioning

confidence: 95%

“…Zfp125 slows down VLDL secretion and mediates most of the metabolic phenotype exhibited by Alb‐D2KO mice (Fernandes et al., ). Zfp125 is induced by Foxo1, a transcription factor that mediates the transition between fed and fasting states in the liver (Fernandes et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…Liver sonicates were obtained as described previously (Fernandes et al., ), mixed with 4× sample loading buffer (Invitrogen, Grand Island, NY), and 20 to 50 μ g protein was fractionated in 4 to 12% NuPAGE Bis‐Tris gels (Life Technologies, Grand Island, NY). Samples were transferred to Immobilon‐FL PVDF transfer membrane (MilliporeSigma, Burlington, MA) and probed overnight with antibodies, as indicated, at a 1:2,500 dilution.…”

Section: Methodsmentioning

confidence: 99%

“…Zfp125 is a transcriptional repressor that reduces the expression of 18 genes involved in intracellular lipid transport, and structure and assembly of VLDL particles. In mice, Zfp125 expression reduces secretion of triglycerides and cholesterol efflux, causing lipid accumulation and liver steatosis (Fernandes et al., ).…”

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confidence: 99%

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Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis

Fonseca

Fernandes

Bocco

et al. 2019

Alcoholism Clin & Exp Res

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Background: A mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of verylow-density lipoprotein.Methods: Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis.Results: The EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOHinduced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOHcontaining diet for the same period of time. Their phenotype was associated with 1.3-to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6-to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH.Conclusions: EtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis

Fonseca

Fernandes

Bocco

et al. 2019

Alcoholism Clin & Exp Res

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Epigenetic developmental programming and intergenerational effects of thyroid hormones

Hernández

Martı́nez

Chaves

et al. 2023

Hormones and Epigenetics

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Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver

Jin

Wahlang

Thapa

et al. 2021

Acta Pharmaceutica Sinica B

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Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and Ahr –/– mice (Taconic) were fed a control diet and exposed to 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) (61 nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets ( Cyp1a1 and Cyp1a2 ) in WT but not Ahr –/– . Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in Ahr –/– . The liver proteome was impacted more so by Ahr –/– genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was Ahr -dependent. Ahr principally regulated liver metabolism ( e . g ., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response ( e . g ., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.

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

Cited by 22 publications

References 25 publications

Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis

Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis

Epigenetic developmental programming and intergenerational effects of thyroid hormones

Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver

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