title: High expression of liver histone deacetylase 3 contributes to high-fat-diet-induced metabolic syndrome by suppressing the PPAR-γ and LXR-α-pathways in E3 rats.
abstract: In the previous experiment, we found that there was a different response between E3 rats and DA.1U rats to high-fat-diet-induced metabolic syndrome (HFD-MetS). The aim of this study was to explore the cause and molecular mechanism of the genetic difference in susceptibility to metabolic syndrome in E3 rats as compared with DA.1U rats. Firstly, a 12-week HFD-MetS model in E3 and DA.1U rats was carried out and assessed. Then, the expression of key insulin signaling molecules, metabolic nuclear receptors, metabolic key enzymes and histone deacetylases (Hdacs) was determined by different methods. Finally, the effects of overexpression and disruption of Hdac3 on metabolic nuclear receptors were analyzed in CBRH-7919 cells and primarily-hepatic cells from DA.1U and E3 rats. We found that E3 rats were susceptible, while DA.1U rats were resisted to HFD-MetS. The expression of liver X receptor α,β (LXR-α,β), farnesoid X receptor (FXR), peroxisome proliferator activated receptor γ (PPAR-γ) and cholesterol 7α-hydroxylase (CYP7A1) increased markedly in DA.1U rat liver, whereas they decreased significantly in E3 rats. The expression of Hdac3 increased by HFD treatment in both E3 and DA.1U rat livers, but the constitutive Hdac3 expression was lower in DA.IU rat liver than in E3 rat liver. Importantly, overexpression of Hdac3 could downregulate the expression of LXR-α, PPAR-γ and CYP7A1 in both CBRH-7919 cells and primarily cultured hepatic cells from DA.IU rats. On the contrary, disruption of Hdac3 by shRNA upregulated the expression of LXR-α, PPAR-γ and CYP7A1 in both CBRH-7919 cells and primarily cultured hepatic cells from E3 rats. The results suggested that a high constitutive expression of Hdac3 inhibiting the expression of PPAR-γ, LXR-α and CYP7A1 in liver contributes to HFD-MetS in E3 rats.
authors.affiliation: Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Li
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.forename: Wuchao
authors.initials: W
authors.lastname: Ren
authors.forename: Juan
authors.initials: J
authors.lastname: Ren
authors.forename: Xi
authors.initials: X
authors.lastname: Lan
authors.forename: Feimiao
authors.initials: F
authors.lastname: Wang
authors.forename: Hongmin
authors.initials: H
authors.lastname: Li
authors.forename: Fujun
authors.initials: F
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Han
authors.forename: Tianbao
authors.initials: T
authors.lastname: Song
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Shemin
authors.initials: S
authors.lastname: Lu
mesh_terms: D000818:Animals; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D020869:Gene Expression Profiling; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D024821:Metabolic Syndrome / Q000201:enzymology / Q000209:etiology*; D009929:Organ Size; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D002790:Cholesterol 7-alpha-Hydroxylase; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D006655:Histone Deacetylases; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D011972:Receptor, Insulin; D047488:Retinoid X Receptors; D000099186:Histone Deacetylase 3; C000605215:Nr1h3 protein, rat; C495683:Slc2a2 protein, rat; C495694:Slc2a4 protein, rat; C532838:CYP7A1 protein, rat