Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity
Biliverdin reductase-A (BVR-A) is a serine/threonine/tyrosine kinase involved in the regulation of insulin signaling. In vitro studies have demonstrated that BVR-A is a substrate of the insulin receptor and regulates IRS1 by avoiding its aberrant activation, and in animal model of obesity the loss o...
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Published in | Biochimica et biophysica acta. Molecular basis of disease Vol. 1865; no. 6; pp. 1490 - 1501 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
Elsevier B.V
01.06.2019
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Subjects | |
Online Access | Get full text |
ISSN | 0925-4439 1879-260X 1879-260X |
DOI | 10.1016/j.bbadis.2019.02.021 |
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Summary: | Biliverdin reductase-A (BVR-A) is a serine/threonine/tyrosine kinase involved in the regulation of insulin signaling. In vitro studies have demonstrated that BVR-A is a substrate of the insulin receptor and regulates IRS1 by avoiding its aberrant activation, and in animal model of obesity the loss of hepatic BVR-A has been associated with glucose/insulin alterations and fatty liver disease. However, no studies exist in humans. Here, we evaluated BVR-A expression levels and activation in peripheral blood mononuclear cells (PBMC) from obese subjects and matched lean controls and we investigated the related molecular alterations of the insulin along with clinical correlates. We showed that BVR-A levels are significantly reduced in obese subjects and associated with a hyper-activation of the IR/IRS1/Akt/GSK-3β/AS160/GLUT4 pathway. Low BVR-A levels also associate with the presence of obesity, metabolic syndrome, NASH and visceral adipose tissue inflammation. These data suggest that the reduction of BVR-A may be responsible for early alterations of the insulin signaling pathway in obesity and in this context may represent a novel molecular target to be investigated for the comprehension of the process of insulin resistance development in obesity.
•Reduced BVR-A protein levels were found in PBMC from obese subjects.•Low BVR-A are associated with reduced IRS1 inhibition.•Reduced IRS1 inhibition leads to insulin signaling hyper-activation.•Insulin signaling hyper-activation preserves euglycemia in obese subjects.•Insulin signaling hyper-activation precedes insulin resistance. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0925-4439 1879-260X 1879-260X |
DOI: | 10.1016/j.bbadis.2019.02.021 |