Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity

Flavia Agata Cimini; Andrea Arena; Ilaria Barchetta; Antonella Tramutola; Valentina Ceccarelli; Chiara Lanzillotta; Mario Fontana; Laura Bertoccini; Frida Leonetti; Danila Capoccia; Gianfranco Silecchia; Claudio Di Cristofano; Caterina Chiappetta; Fabio Di Domenico; Marco Giorgio Baroni; Marzia Perluigi; Maria Gisella Cavallo; Eugenio Barone

doi:10.1016/j.bbadis.2019.02.021

Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity

Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1490-1501. doi: 10.1016/j.bbadis.2019.02.021. Epub 2019 Feb 28.

Authors

Flavia Agata Cimini¹, Andrea Arena², Ilaria Barchetta¹, Antonella Tramutola², Valentina Ceccarelli¹, Chiara Lanzillotta², Mario Fontana², Laura Bertoccini¹, Frida Leonetti¹, Danila Capoccia¹, Gianfranco Silecchia³, Claudio Di Cristofano³, Caterina Chiappetta³, Fabio Di Domenico², Marco Giorgio Baroni¹, Marzia Perluigi², Maria Gisella Cavallo⁴, Eugenio Barone⁵

Affiliations

¹ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
² Department of Biochemical Sciences "A. Rossi-Fanelli" Sapienza University of Rome, Rome, Italy.
³ Department of Medical-Surgical Sciences and Bio-Technologies, Sapienza University of Rome, Rome, Italy.
⁴ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: [email protected].
⁵ Department of Biochemical Sciences "A. Rossi-Fanelli" Sapienza University of Rome, Rome, Italy. Electronic address: [email protected].

PMID: 30826467
DOI: 10.1016/j.bbadis.2019.02.021

Abstract

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.

Keywords: Biliverdin reductase-a; Insulin signaling; Metabolic disorders; Obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Bariatric Surgery / methods
Case-Control Studies
Cholesterol, HDL / blood
Cholesterol, LDL / blood
Female
GTPase-Activating Proteins / blood
GTPase-Activating Proteins / genetics
Gene Expression Regulation*
Glucose Transporter Type 4 / blood
Glucose Transporter Type 4 / genetics
Glycogen Synthase Kinase 3 beta / blood
Glycogen Synthase Kinase 3 beta / genetics
Humans
Insulin / blood*
Insulin Receptor Substrate Proteins / blood
Insulin Receptor Substrate Proteins / genetics
Insulin Resistance / genetics*
Intra-Abdominal Fat / metabolism
Intra-Abdominal Fat / pathology
Leukocytes, Mononuclear / metabolism
Leukocytes, Mononuclear / pathology
Male
Middle Aged
Obesity / blood
Obesity / genetics*
Obesity / pathology
Obesity / surgery
Oxidoreductases Acting on CH-CH Group Donors / blood
Oxidoreductases Acting on CH-CH Group Donors / deficiency
Oxidoreductases Acting on CH-CH Group Donors / genetics*
Primary Cell Culture
Proto-Oncogene Proteins c-akt / blood
Proto-Oncogene Proteins c-akt / genetics
Signal Transduction / genetics*
TOR Serine-Threonine Kinases / blood
TOR Serine-Threonine Kinases / genetics
Triglycerides / blood

Substances

Cholesterol, HDL
Cholesterol, LDL
GTPase-Activating Proteins
Glucose Transporter Type 4
IRS1 protein, human
Insulin
Insulin Receptor Substrate Proteins
SLC2A4 protein, human
TBC1D4 protein, human
Triglycerides
Oxidoreductases Acting on CH-CH Group Donors
BLVRA protein, human
MTOR protein, human
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases