Hepatic Gene Expression in Morbidly Obese Women: Implications for Disease Susceptibility

Elam, Marshall B.; Cowan, George S M; Rooney, Robert J.; Hiler, Magdalena; Yellaturu, Chandrahasa R.; Deng, Xiong; Howell, George; Park, Edwards A.; Gerling, Ivan; Patel, Divyan; Corton, J. Christopher; Cagen, Lauren M.; Wilcox, Henry G.; Gandhi, Malay; Bahr, M.; Allan, Micheal C.; Wodi, Linus A.; Cook, George A.; Hughes, Thomas A.; Raghow, Rajendra

doi:10.1038/oby.2009.49

Cited by 37 publications

(39 citation statements)

References 57 publications

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“…Recent reports revealed that the increased in the synthesis of fatty acids enhances HCV replication (Kapadia and Chisari, 2005). Our results showed upregulation of ELOVL2 gene and is in agreement with Elam et al (2009) who reported ELOVL2 overexpression in morbidly obese women.…”

Section: Discussionsupporting

confidence: 82%

Molecular Prognostic Profile of Egyptian HCC Cases Infected with Hepatitis C Virus

Zekri

Hassan²,

Bahnassy³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: Hepatocellular carcinoma (HCC) is a common and aggressive malignancy. Despite of the improvements in its treatment, HCC prognosis remains poor due to its recurrence after resection. This study provides complete genetic profile for Egyptian HCC. Genome-wide analyses were performed to identify the predictive signatures. Patients and Methods: Liver tissue was collected from 31 patients with diagnosis of HCC and gene expression levels in the tumours and their adjacent non-neoplastic tissues samples were studied by analyzing changes by microarray then correlate these with the clinico-pathological parameters. Genes were validated in an independent set by qPCR. The genomic profile was associated with genetic disorders and cancer focused on gene expression, cell cycle and cell death. Molecular profile analysis revealed cell cycle progression and arrest at G2/M, but progression to mitosis; unregulated DNA damage check-points, and apoptosis. Result: Nine hundred fifty eight transcripts out of the 25,000 studied cDNAs were differentially expressed; 503 were up-regulated and 455 were down-regulated. A total of 19 pathways were up-regulated through 27 genes and 13 pathways were down-regulated through 19 genes. Thirty-seven genes showed significant differences in their expression between HCC cases with high and low Alpha Feto Protein (AFP ≥600 IU/ml). The validation for the microarray was done by real time PCR assay in which PPP3CA, ATG-5, BACE genes showed down-regulation and ABCG2, RXRA, ELOVL2, CXR3 genes showed up-regulation. cDNA microarrays showed that among the major upregulated genes in HCC are sets. Conclusion: The identified genes could provide a panel of new diagnostic and prognostic aids for HCC.

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Section: Discussionsupporting

confidence: 82%

Molecular Prognostic Profile of Egyptian HCC Cases Infected with Hepatitis C Virus

Zekri

Hassan²,

Bahnassy³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…This draws support from a previous report that observed an elevation in the expression of REDD1 from liver tissue of morbidly obese humans (22). Glucocorticoids are elevated in the obese under both fasted and fed conditions (3,49,80).…”

Section: Discussionsupporting

confidence: 76%

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Williamson

Dungan

Mahmoud

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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-The objective of this study was to establish whether alterations in the REDD1-mTOR axis underlie skeletal muscle insensitivity to insulin in Type 2 diabetic (T2D), obese individuals. Vastus lateralis muscle biopsies were obtained from lean, control and obese, T2D subjects under basal and after a 2-h hyperinsulinemic (40 mU·m Ϫ2 ·min Ϫ1 )-euglycemic (5 mM) clamp. Muscle lysates were examined for total REDD1, and phosphorylated Akt, S6 kinase 1 (S6K1), 4E-BP1, ERK1/2, and MEK1/2 via Western blot analysis. Under basal conditions [(-) insulin], T2D muscle exhibited higher S6K1 and ERK1/2 and lower 4E-BP1 phosphorylation (P Ͻ 0.05), as well as elevations in blood cortisol, glucose, insulin, glycosylated hemoglobin (P Ͻ 0.05) vs. lean controls. Following insulin infusion, whole body glucose disposal rates (GDR; mg/kg/ min) were lower (P Ͻ 0.05) in the T2D vs. the control group. The basal-to-insulin percent change in REDD1 expression was higher (P Ͻ 0.05) in muscle from the T2D vs. the control group. Whereas, the basal-to-insulin percent change in muscle Akt, S6K1, ERK1/2, and MEK1/2 phosphorylation was significantly lower (P Ͻ 0.05) in the T2D vs. the control group. Findings from this study propose a REDD1-regulated mechanism in T2D skeletal muscle that may contribute to whole body insulin resistance and may be a target to improve insulin action in insulin-resistant individuals.glucocorticoid; insulin resistance; mTOR; signaling TWO-THIRDS OF THE UNITED STATES has a 25% or greater prevalence of obesity (54), which places increased demand and cost on the health care system. Of the numerous comorbidities associated with obesity, the development of insulin resistance and Type 2 diabetes (T2D) are major concern for obese individuals, leading to overall reductions in metabolic flexibility (50). This becomes more of a concern, since the population of obese individuals is expanding in all age groups. Findings from the National Health and Nutrition Examination Survey data (68,69) show that skeletal muscle mass is fundamental for insulin sensitivity. Skeletal muscle mass is lower in the obese when expressed relative to total body mass vs. a lean individual and has a high pervasiveness of ectopic lipid within skeletal muscle that contributes to reduced insulin action (27,50). Among other factors, elevated endogenous glucocorticoid concentrations contribute to insulin resistance in the obese and T2D (58, 74).Insulin activation of the insulin receptor substrate 1 (IRS-1), phosphatidyl-inositol-3 kinase (PI3K), Ak strain transforming (Akt), and the ERK 1/2 pathways are essential for the regulation of cellular glucose uptake, proliferation, and growth. Akt and ERK1/2 activation increases GTPase function of the Ras homolog enriched in brain (Rheb) protein toward the mechanistic target of rapamycin (mTOR; also known as mammalian target of rapamycin) by inactivating the repressive effects of the tuberous sclerosis complex (TSC). The TSC complex remains central to the integration of signaling inputs from Akt, ERK1/2, and AMPK (32, 44,...

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“…oxygen species accumulation is in general associated with cellular insulin resistance (29), increased REDD1 expression in response to insulin could participate to the development of insulin resistance. This latter hypothesis is reinforced by the observation that expression of REDD1 is significantly higher in liver of morbidly obese patients (30).…”

Section: Discussionsupporting

confidence: 55%

Insulin Induces REDD1 Expression through Hypoxia-inducible Factor 1 Activation in Adipocytes

Regazzetti¹,

Bost²,

Marchand-Brustel³

et al. 2010

Journal of Biological Chemistry

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REDD1 (regulated in development and DNA damage responses) is essential for the inhibition of mTORC1 (mammalian target of rapamycin complex) signaling pathway in response to hypoxia. REDD1 expression is regulated by many stresses such as hypoxia, oxidative stress, and energy depletion. However, the regulation of REDD1 expression in response to insulin remains unknown. In the present study, we demonstrate that in murine and in human adipocytes, insulin stimulates REDD1 expression. Insulin-induced REDD1 expression occurs through phosphoinositide 3-kinase/mTOR-dependent pathways. Moreover, using echinomycin, a hypoxia-inducible factor 1 (HIF-1) inhibitor, and HIF-1␣ small interfering RNA, we demonstrate that insulin stimulates REDD1 expression only through the transcription factor HIF-1. In conclusion, our study shows that insulin stimulates REDD1 expression in adipocytes. Mammalian target of rapamycin (mTOR)2 integrates several extrinsic signals that regulate cell growth and metabolism. mTOR is present in two multiprotein complexes: mTORC1, consisting of mTOR, Raptor, PRAS40, and mLST8/G␤L; and mTORC2, composed of mTOR, LST8/ G␤L, Rictor, mSin1, and Protor. mTORC1 regulates cell growth through S6 kinase 1 and eIF-4E-binding protein 1, whereas mTORC2 modulates cell survival by phosphorylating Akt/protein kinase B. mTOR complexes are regulated by TSC1/TCS2, a GTPase-activating protein for the Rasrelated small G protein Rheb, which regulates mTOR activation (1).In response to insulin and growth factors, TSC2 is phosphorylated and inhibited by Akt/protein kinase B, leading to activation of mTORC1. In response to stress, TSC2 is activated by phosphorylation through the LKB1/AMPK pathway, which contributes to mTORC1 inhibition. Several proteins are involved in the regulation of mTORC1 activity, such as FKBP38, PRAS40, DEPTOR, or REDD1 (2-4).REDD1 (for regulated in development and DNA damage responses), also known as RTP801/Dig2/DDIT4, is required for down-regulation of mTORC1 in response to hypoxia (5). Indeed, REDD1 overexpression is sufficient to inhibit mTOR activation, whereas loss of REDD1 blocks mTOR inhibition by hypoxia. REDD1 controls mTORC1 activity through 14-3-3 proteins. 14-3-3 proteins associate and inhibit TSC2 through direct binding. REDD1, induced by hypoxia, associates with 14-3-3, relieving TSC2 inhibition (6).REDD1 is up-regulated in response to many stresses such as hypoxia, oxidative stress, endoplasmic reticulum stress, multiple DNA damage stimuli, and energy depletion. Depending on the physiological context, its transcription is controlled by several transcription factors. Indeed, REDD1 is expressed through hypoxia-inducible factor 1 (HIF-1), in MCF-7 cancer cells under hypoxic condition cells (7,8). REDD1 is also regulated by activating transcription factor-4 in response to endoplasmic reticulum stress (9 -11), by p53 and p63 during DNA damage (12), and by Elk-1 and CCAAT/enhancer-binding protein in response to arsenic in keratinocytes (13).Insulin is a potent activator of mTOR, which regulates v...

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Hepatic Gene Expression in Morbidly Obese Women: Implications for Disease Susceptibility

Cited by 37 publications

References 57 publications

Molecular Prognostic Profile of Egyptian HCC Cases Infected with Hepatitis C Virus

Molecular Prognostic Profile of Egyptian HCC Cases Infected with Hepatitis C Virus

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Insulin Induces REDD1 Expression through Hypoxia-inducible Factor 1 Activation in Adipocytes

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