Dichotomic role of heparanase in a murine model of metabolic syndrome
- PDF / 1,033,383 Bytes
- 10 Pages / 595.276 x 790.866 pts Page_size
- 11 Downloads / 160 Views
Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Dichotomic role of heparanase in a murine model of metabolic syndrome Esther Hermano1 · Françoise Carlotti2 · Alexia Abecassis1 · Amichay Meirovitz1 · Ariel M. Rubinstein1 · Jin‑Ping Li3 · Israel Vlodavsky4 · Ton J. Rabelink2 · Michael Elkin1,5 Received: 13 May 2020 / Revised: 17 September 2020 / Accepted: 28 September 2020 © Springer Nature Switzerland AG 2020
Abstract Heparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune diabetes is well documented, its association with metabolic syndrome/type 2 diabetes attracted less attention. Our research was undertaken to elucidate the significance of heparanase in impaired glucose metabolism in metabolic syndrome and early type 2 diabetes. Here, we report that heparanase exerts opposite effects in insulin-producing (i.e., islets) vs. insulin-target (i.e., skeletal muscle) compartments, sustaining or hampering proper regulation of glucose homeostasis depending on the site of action. We observed that the enzyme promotes macrophage infiltration into islets in a murine model of metabolic syndrome, and fosters β-cell-damaging properties of macrophages activated in vitro by components of diabetogenic/obese milieu (i.e., fatty acids). On the other hand, in skeletal muscle (prototypic insulin-target tissue), heparanase is essential to ensure insulin sensitivity. Thus, despite a deleterious effect of heparanase on macrophage infiltration in islets, the enzyme appears to have beneficial role in glucose homeostasis in metabolic syndrome. The dichotomic action of the enzyme in the maintenance of glycemic control should be taken into account when considering heparanase-targeting strategies for the treatment of diabetes. Keywords Heparanase · Diabetes · Obesity · Macrophages · Insulin resistance Abbreviations ECM Extracellular matrix HS Heparan sulfate AGE Advanced glycation end products HFD High-fat diet CD Control diet Hpse-KO Heparanase-deficient mice Esther Hermano, Françoise Carlotti, Alexia Abecassis contributed equally to this work. * Michael Elkin [email protected] 1
Department of Oncology, Sharett Institute, HadassahHebrew University Medical Center, 91120 Jerusalem, Israel
2
Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
3
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
4
Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel
5
Hebrew University Medical School, 91120 Jerusalem, Israel
sFA Saturated fatty acids uFA Unsaturated fatty acids
Introduction Extracellular matrix (ECM) and its remodeling emerged as essential determinants in the regulation of metabolic status [1–5]. The role of the ECM-degrading enzyme heparanase in diabetes and its complications has been actively investigated during the last
Data Loading...
