Deleted in Breast Cancer 1 (DBC1) Protein Regulates Hepatic Gluconeogenesis

Nin, Verónica; Chini, Claudia C.S.; Escande, Carlos; Capellini, Verena Kise; Chini, Eduardo N.

doi:10.1074/jbc.m113.512913

Cited by 19 publications

(18 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DBC1 serves as an endogenous inhibitor HDAC3 [38], and it plays a crucial physiological role as a modulator of epigenetics and metabolic function. In an earlier study, DBC1 knockout mice showed increased expression of PEPCK and gluconeogenesis, whereas over expression DBC1 reduced the PEPCK expression [39]. As we saw a negative correlation between HDAC3 activity and mRNA levels of DBC1 in our study, it appears that the regulatory circuit of endogenous control of HDAC3 could be somehow lost in patients with type 2 diabetes and this needs to be studied in-depth in future investigations.…”

Section: Discussionsupporting

confidence: 53%

Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes

et al. 2016

View full text Add to dashboard Cite

BackgroundA role of proinflammation has been implicated in the pathogenesis of diabetes, but the up-stream regulatory signals and molecular signatures are poorly understood. While histone modifications such as changes in histone deacetylase (HDAC) are emerging as novel epigenetic biomarkers, there is lack of studies to demonstrate their clinical relevance in diabetes. Therefore, we investigated the extent of HDAC machinery and inflammatory signals in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes mellitus (T2DM) compared to control subjects.Results HDAC3 activity was significantly (p < 0.05) increased in patients with T2DM compared to control subjects. While subtypes of HDACs were differentially expressed at their transcriptional levels in patients with type 2 diabetes, the most prominent observation is the significantly (p < 0.05) elevated messenger RNA (mRNA) levels of HDAC3. Expression levels of Sirt1 which represents the class III HDAC were decreased significantly in T2DM (p < 0.05). Plasma levels of both TNF-α and IL-6 were significantly higher (p < 0.05) in patients with type 2 diabetes compared to control subjects. Among the proinflammatory mediators, the mRNA expression of MCP-1, IL1-β, NFκB, TLR2, and TLR4 were also significantly (p < 0.05) increased in T2DM. Transcriptional levels of DBC1 (deleted in breast cancer 1, which is a negative regulator of HDAC3) were seen significantly reduced in PBMCs from T2DM. Interestingly, HDAC3 activity/HDAC3 mRNA levels positively correlated to proinflammation, poor glycemic control, and insulin resistance.ConclusionsStriking message from this study is that while looking for anti-inflammatory strategies and drugs with novel mode of action for T2DM, discovering and designing specific inhibitors targeted to HDAC3 appears promising.

show abstract

Section: Discussionsupporting

confidence: 53%

Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In the latter model, female mice developed a “fit obese” phenotype, i.e., obesity with insulin sensitivity, and reduced adipocyte lipolysis (Escande et al, 2015). Neither in two previous reports (Escande et al, 2015; Nin et al, 2014), nor in our study are males protected from diet-induced insulin resistance, raising the possibility of sex-dimorphic actions of Dbc1. We did not observe protection from diet-induced steatosis on chow/HFD feeding (not shown) or through Scd1 inhibition (Figure S5), possibly due to different knockout strategies or experimental conditions.…”

Section: Discussioncontrasting

confidence: 99%

“…The metabolic abnormalities in our Dbc1 −/− mice are largely consistent with those in knockouts generated by genetrap methodology (Escande et al, 2010; Escande et al, 2015; Nin et al, 2014). In the latter model, female mice developed a “fit obese” phenotype, i.e., obesity with insulin sensitivity, and reduced adipocyte lipolysis (Escande et al, 2015).…”

Section: Discussionsupporting

confidence: 78%

Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions

Kon

Zhao

et al. 2015

Cell Reports

View full text Add to dashboard Cite

SUMMARY Obesity is associated with higher incidence of cancer but the predisposing mechanisms remain poorly understood. The NAD+–dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. To date, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin-resistance. Dbc1 deficiency promoted SirT1-dependent gain-of-function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids. The metabolic abnormalities in Dbc1−/− mice were reversed by ablation of hepatic SirT1 or by inhibition of Scd1 activity. Furthermore, loss of Dbc1 impaired master tumor suppressor p53 activation and treatment of Scd1 inhibitor extended survival of tumorigenic TP53−/− mice by decreasing tumor-related death. Together, our findings illustrate a shared mechanism of obesity and tumor progression through hepatic SirT1 gain-of-function in a metabolic control step, with potential therapeutic implications.

show abstract

“…Previous studies demonstrated that DBC1 might modulate liver gluconeogenesis through binding and regulating Rev-erbα, SIRT1, and phosphoenolpyruvate carboxykinase (PEPCK) (Nin et al, 2014). The higher expression of DBC1 compared to DBC1a (Fig.8 c) showed that the DBC1 was the main isoform in liver.…”

Section: Discussionmentioning

confidence: 82%

“…The higher expression of DBC1 compared to DBC1a (Fig.8 c) showed that the DBC1 was the main isoform in liver. Overexpression of DBC1 decreases mRNA and protein levels of PEPCK, while DBC1 knockout mice displayed the converse result (Nin et al, 2014).…”

Section: Discussionmentioning

confidence: 98%

Novel splice isoforms of dairy goat DBC1 and their diverse mRNA expression profiles

Zhang

et al. 2015

Small Ruminant Research

View full text Add to dashboard Cite

Deleted in Breast Cancer 1 (DBC1) Protein Regulates Hepatic Gluconeogenesis

Cited by 19 publications

References 41 publications

Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes

Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes

Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions

Novel splice isoforms of dairy goat DBC1 and their diverse mRNA expression profiles

Contact Info

Product

Resources

About