Effects of Diabetes Mellitus on Hepatocyte Nuclear Factor 1 Decrease Albumin Gene Transcription

Barrera-Hernandez, Gonzalo; Wanke, Irene; Wong, Norman C.W.

doi:10.1074/jbc.271.17.9969

Cited by 19 publications

(21 citation statements)

References 63 publications

(62 reference statements)

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“…To our knowledge this is only the second transcription factor shown to be altered in expression as a result of diabetes, the other being hepatic nuclear factor-1 [28]. What is even more intriguing about our results relates to the fact that C/EBPa mRNA can be translated into several different protein products through selection of alternate initiation sites [18,19].…”

Section: Discussionmentioning

confidence: 77%

Hepatic expression of CCAAT/enhancer binding protein α: hormonal and metabolic regulation in rats

1997

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The a -isoform of the CCAAT/enhancer binding protein (C/EBP) is a member of the basic region-leucine zipper family of transcription factors. Initially it was identified as a liver-enriched protein, but further analysis indicated that it was also highly expressed in adipose and placental tissue, and at lower levels in small intestine and lung [1]. With the exception of lung, all of these tissues play a major role in different aspects of energy balance. Liver and adipose tissue are major sites for the storage and release of metabolic fuels, the small intestine is involved in fuel uptake from the diet, and the placenta plays a critical role in fetal nutrition. The expression in lung can also be explained in this context, since it is actively involved in the synthesis of surfactant lipids. It is of further interest that C/EBPa binds to and transactivates several metabolically important gene promoters, including phosphoenolpyruvate carboxykinase [3], serum albumin [4], the insulin responsive GLUT2, GLUT4 [5], alcohol dehydrogenase [6], several adipocyte-specific genes [7], and C/EBPa itself [8].While several C/EBP isoforms co-exist in liver, with the two most abundant being the a -and b -isoforms [9], data from knockout mice indicate that C/ EBPa plays a significantly more important role in the regulation of metabolism than the b -isoform. Mice homozygous for the targeted deletion in the C/EBPa gene have no detectable amounts of liver glycogen,

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Section: Discussionmentioning

confidence: 77%

Hepatic expression of CCAAT/enhancer binding protein α: hormonal and metabolic regulation in rats

1997

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“…Our finding is consistent with the mice work wherein we observed increased albumin levels in CICs from diabetic mice, which in turn was reduced when diabetic mice were treated with aminoguanidine. It has also been reported previously that albumin transcription is reduced in diabetes mellitus (43) and reduced serum albumin levels were reported in subjects showing heavy proteinuria (44). Therefore, it is possible that, AGE-modification-induced formation of CICs acts as a major contributor to the reduction in serum albumin levels in addition to proteinuria over long-standing hyperglycemic conditions.…”

Section: Elevated Human Serum Albumin In Cics Of Plasma From Prediabementioning

confidence: 94%

Proteomic Insight Reveals Elevated Levels of Albumin in Circulating Immune Complexes in Diabetic Plasma

Bhat

Jagadeeshaprasad

Patil

et al. 2016

Molecular & Cellular Proteomics

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A Hyperglycemic condition in diabetes promotes formation of advanced glycation end products, which are known to elicit immune response and form complexes with immunoglobulins called circulating immune complexes. To investigate the involvement of advanced glycation end product (AGE)-modified proteins in the elicitation of an immune response, circulating immune complexes were isolated and proteins associated were identified and characterized. Label-free-based mass spectrometric analysis of circulating immune complexes in clinical plasma of prediabetic, newly diagnosed diabetes, and diabetic microalbuminurea revealed elevated levels of serum albumin in the circulating immune complexes, which were also observed to be AGE modified. Further, to examine the role of glycation, circulating immune complexes were analyzed in the streptozotocin-induced diabetic mice treated with or without aminoguanidine, a prototype glycation inhibitor. Mass spectrometric analysis of circulating immune complexes showed elevated levels of serum albumin in plasma from diabetic mice over that of control animals. Aminoguanidine-treated diabetic mice displayed decreased AGE modification of plasma albumin, accompanied by a reduced level of albumin in the circulating immune complexes. In addition, elevated levels of proinflammatory cytokines such as IL-1b, IL-2, and TNF-alpha were observed in diabetes, which were reduced with aminoguanidine treatment, suggesting the involvement of glycation in the immune response.

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“…Among the great number of pathologies possibly related to an alteration of the redox status, only a few, such as diabetes, have been linked to reduced transcription of the albumin gene in experimental models. 52 Moreover, when albuminuria occurs, such as in the nephrotic syndrome, hypoalbuminemia might actually be in part due to an inability of the liver to increase its albumin synthesis. These situations, which are related to a decrease in the antioxidant defense, could be due to the presence of high levels of circulating Ox-LDLs.…”

Section: Discussionmentioning

confidence: 99%

“…The albumin promoter is well known to interact with the hepatocyte nuclear factor-1 transcription factor, which plays a pivotal role in mediating liver-specific transcription of the gene. 52 Further specific studies should be addressed to determine whether sterol regulatory element binding protein 1 or 2 can interact with the albumin promoter or whether Ox-LDLs, lysoderivatives, and oxysterols can affect hepatocyte nuclear factor-1 levels in HepG2 cells.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Oxysterols and Lysophosphatidylcholine in the Oxidized LDL–Induced Impairment of Serum Albumin Synthesis by HEPG2 Cells

Bourdon

Loreau

Davignon

et al. 2000

ATVB

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Abstract-Oxidized low density lipoproteins (Ox-LDLs) are increasingly thought to be a key element in atherogenesis. We have previously reported that serum albumin has important antioxidant properties and that a reduced synthesis of albumin may represent a crucial point in the overall antioxidant defense. In the present work, we aimed at determining whether Ox-LDL could modulate albumin synthesis in cultured human hepatocytes (HepG2 cells). With the use of enzyme immunoassay and radiolabeled leucine incorporation followed by specific immunoprecipitation, Ox-LDL was found to lead to a dose-dependent decrease in albumin secretion. Moreover, the protein synthesis and mRNA levels were decreased in the presence of Ox-LDL, as assessed by Northern blot analysis. Because oxysterols and lysophospholipids are key components of Ox-LDL, we tested the effects of oxysterols (7-ketocholesterol and 25-hydroxycholesterol) and lysophosphatidylcholine on albumin secretion and expression. In our experimental conditions, we found that incubations with oxysterols or lysophosphatidylcholine at pathophysiological concentrations similar to those measured in Ox-LDLs reproduced the above-mentioned inhibitory effects on albumin synthesis. On the basis of our in vitro data, we propose that this newly described biological effect of Ox-LDL might partly explain the findings of epidemiological studies indicating that reduced levels of serum albumin are associated with increased mortality. (Arterioscler Thromb Vasc

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Effects of Diabetes Mellitus on Hepatocyte Nuclear Factor 1 Decrease Albumin Gene Transcription

Cited by 19 publications

References 63 publications

Hepatic expression of CCAAT/enhancer binding protein α: hormonal and metabolic regulation in rats

Hepatic expression of CCAAT/enhancer binding protein α: hormonal and metabolic regulation in rats

Proteomic Insight Reveals Elevated Levels of Albumin in Circulating Immune Complexes in Diabetic Plasma

Involvement of Oxysterols and Lysophosphatidylcholine in the Oxidized LDL–Induced Impairment of Serum Albumin Synthesis by HEPG2 Cells

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