Hepatic steatosis in transgenic mice overexpressing human histone deacetylase 1

Wang, Ai Guo; Seo, Sang-Beom; Moon, Hyung Bae; Shin, Hye Jun; Kim, Dong Hoon; Kim, Jin Man; Lee, Tae Hoon; Kwon, Ho Jeong; Yu, Dae Yeul; Lee, Dong Seok

doi:10.1016/j.bbrc.2005.02.179

Cited by 16 publications

(16 citation statements)

References 21 publications

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“…Our previous finding of increased hepatic triglyceride deposition (10) and current finding of reduced PKC activation in rats exposed to alcohol in utero agree with this study and suggest that other factors may be involved in hepatic steatosis in this rat model. One such factor is HDAC1, whose increased expression has been reported to cause steatosis in mice (41).…”

Section: Discussionmentioning

confidence: 99%

“…It is not known whether TRB3 is also acetylated. It is also interesting that HDAC1 is associated with liver steatosis (41).…”

mentioning

confidence: 99%

“…Besides gene expression, however, recent studies suggest that posttranslational protein modifications play an important role in the regulation of gluconeogenesis and liver steatosis. For example, the transcriptional coactivator peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣), which regulates gluconeogenic enzymes, is controlled by the histone deacetylase (HDAC) SIRT1, which is posttranslationally induced by a nutrient signaling response mediated by pyruvate (32), whereas mice overexpressing HDAC1 exhibit a high incidence of hepatic steatosis (41). We have previously shown that pyruvate injection results in a dramatic blood glucose rise in alcoholexposed rat offspring (44,45), implying that PGC-1␣ deacetylation by SIRT1 is likely to be active in these animals.…”

mentioning

confidence: 99%

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Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring

Yao¹,

Nyomba²

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Prenatal alcohol exposure (EtOH) results in insulin resistance in rats of both sexes with increased expression of hepatic gluconeogenic genes and glucose production. To investigate whether hepatic insulin signaling is defective, we studied 3-mo-old female offspring of dams that were given EtOH during pregnancy compared with those from pair-fed and control dams. We performed an intraperitoneal pyruvate tolerance test, determined the phosphorylation status of hepatic phosphoinositide-dependent protein kinase-1 (PDK1), Akt, and PKCzeta before and after intravenous insulin bolus, and measured mRNA and in vivo acetylation of TRB3 (tribbles 3) and PTEN (phosphatase and tensin homolog deleted on chromosome ten) as well as the expression of the histone acetylase (HAT) PCAF (p300/CREB-binding protein-associated factor), histone deacetylase-1 (HDAC1), and HAT and HDAC activities. In EtOH compared with pair-fed and control offspring, basal and pyruvate-induced blood glucose was increased, insulin-induced PDK1, Akt, and PKCzeta phosphorylation was reduced, and expression of PTEN and TRB3 was increased while their acetylation status was decreased in association with increased HDAC and decreased HAT activities. Thus female adult rats prenatally exposed to EtOH have increased gluconeogenesis, reduced insulin signaling, and increased PTEN and TRB3 expression in the liver. In addition, PTEN and TRB3 are hypoacetylated, which can contribute to Akt-inhibiting activity. These results suggest that hepatic insulin resistance in rats prenatally exposed to EtOH is explained, at least in part, by increased PTEN and TRB3 activity due to both increased gene expression and reduced acetylation.

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Section: Discussionmentioning

confidence: 99%

“…It is not known whether TRB3 is also acetylated. It is also interesting that HDAC1 is associated with liver steatosis (41).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring

Yao¹,

Nyomba²

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…For example, HDAC1 stimulates angiogenesis in epithelial cells (Kim et al ., 2001), an event associated with retinal disease and other age-associated pathologies (Gariano & Gardner, 2005), and generates hepatic steatosis in mice (Wang et al ., 2005), a pathological condition associated with increased age, body weight, and fibrosis (Perumalswami et al ., 2006). …”

Section: Discussionmentioning

confidence: 99%

Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi

et al. 2007

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Summary The retinoblastoma (RB)/p16INK4a pathway regulates senescence of human melanocytes in culture and oncogeneinduced senescence of melanocytic nevi in vivo . This senescence response is likely due to chromatin modifications because RB complexes from senescent melanocytes contain increased levels of histone deacetylase (HDAC) activity and tethered HDAC1. Here we show that HDAC1 is prominently detected in p16 INK4a -positive, senescent intradermal melanocytic nevi but not in proliferating, recurrent nevus cells that localize to the epidermal/ dermal junction. To assess the role of HDAC1 in the senescence of melanocytes and nevi, we used tetracyclinebased inducible expression systems in cultured melanocytic cells. We found that HDAC1 drives a sequential and cooperative activity of chromatin remodeling effectors, including transient recruitment of Brahma (Brm1) into RB/HDAC1 mega-complexes, formation of heterochromatin protein 1β β β β (HP1β β β β )/SUV39H1 foci, methylation of H3-K9, stable association of RB with chromatin and significant global heterochromatinization. These chromatin changes coincide with expression of typical markers of senescence, including the senescent-associated β β β β -galactosidase marker. Notably, formation of RB/HP1β β β β foci and early tethering of RB to chromatin depends on intact Brm1 ATPase activity. As cells reached senescence, ejection of Brm1 from chromatin coincided with its dissociation from HP1β β β β /RB and relocalization to protein complexes of lower molecular weight. These results provide new insights into the role of the RB pathway in regulating cellular senescence and implicate HDAC1 as a likely mediator of early chromatin remodeling events.

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“…In this respect, HDAC-3 absence in zebrafish leads to abnormalities in liver development, [39] whilst conditioned deletion of HDAC-3 in mice induces severe disruption of carbohydrate and lipid metabolism, resulting in organ hypertrophy and hepatocellular damage [40]. HDAC-1 overexpression in transgenic mice, on the other hand, results in a high incidence of hepatic steatosis and nuclear pleomorphism concomitant with altered expression of genes involved in cell cycle, apoptosis, and lipid metabolism such as p53, PPARc, Bak and p21 [41,42]. Also, a number of studies provide evidence for the involvement of HDACs and HATs in the transcriptional regulation of liver-specific genes by LETFs.…”

Section: Classification Of Histone Deacetylases and Their Role In Difmentioning

confidence: 97%

Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation and stem cell reprogrammation

Snykers

Henkens

Rop

et al. 2009

Journal of Hepatology

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Controlling both growth and differentiation of stem cells and their differentiated somatic progeny is a challenge in numerous fields, from preclinical drug development to clinical therapy. Recently, new insights into the underlying molecular mechanisms have unveiled key regulatory roles of epigenetic marks driving cellular pluripotency, differentiation and self-renewal/proliferation. Indeed, the transcription of genes, governing cell-fate decisions during development and maintenance of a cell's differentiated status in adult life, critically depends on the chromatin accessibility of transcription factors to genomic regulatory and coding regions. In this review, we discuss the epigenetic control of (liver-specific) gene-transcription and the intricate interplay between chromatin modulation, including histone (de)acetylation and DNA (de)methylation, and liver-enriched transcription factors. Special attention is paid to their role in directing hepatic differentiation of primary hepatocytes and stem cells in vitro.

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Hepatic steatosis in transgenic mice overexpressing human histone deacetylase 1

Cited by 16 publications

References 21 publications

Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring

Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring

Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi

Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation and stem cell reprogrammation

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