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Open AccessArticle

Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men

1
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Auf’m Hennekamp 65, 40225 Düsseldorf, Germany
2
German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
3
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
4
Department of Endocrinology, Ghent University Hospital, 9000 Ghent, Belgium
5
Department of Gastrointestinal Surgery, Ghent University Hospital, 9000 Ghent, Belgium
6
Clinical Research Centre, Department of Internal Medicine I, University Hospital Aachen, 52074 Aachen, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(11), 4144; https://doi.org/10.3390/ijms21114144
Received: 14 May 2020 / Revised: 4 June 2020 / Accepted: 8 June 2020 / Published: 10 June 2020
Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters. View Full-Text
Keywords: NAFLD; fatty liver metabolism; fatty liver progression; de novo lipogenesis; IGFBP2; IGF system; methylation; SREBP-1c NAFLD; fatty liver metabolism; fatty liver progression; de novo lipogenesis; IGFBP2; IGF system; methylation; SREBP-1c
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Fahlbusch, P.; Knebel, B.; Hörbelt, T.; Barbosa, D.M.; Nikolic, A.; Jacob, S.; Al-Hasani, H.; Van de Velde, F.; Van Nieuwenhove, Y.; Müller-Wieland, D.; Lapauw, B.; Ouwens, D.M.; Kotzka, J. Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men. Int. J. Mol. Sci. 2020, 21, 4144.

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