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Sulforaphane improves disrupted ER-mitochondria interactions and suppresses exaggerated hepatic glucose production

Journal article
Authors E. Tubbs
A. S. Axelsson
G. Vial
C. B. Wollheim
J. Rieusset
Anders H. Rosengren
Published in Molecular and Cellular Endocrinology
Volume 461
Issue C
Pages 205-214
ISSN 0303-7207
Publication year 2018
Published at Institute of Neuroscience and Physiology
Pages 205-214
Language en
Links dx.doi.org/10.1016/j.mce.2017.09.01...
Keywords Mitochondria-associated ER membranes, Type 2 diabetes, Sulphoraphane, endoplasmic-reticulum stress, induced insulin-resistance, type-2, diabetes-mellitus, high-fat diet, oxidative stress, dysfunction, nrf2, disease, cells, lipogenesis, Cell Biology, Endocrinology & Metabolism, fronzo ra, 1989, metabolism-clinical and experimental, v38, p387
Subject categories Endocrinology and Diabetes

Abstract

Aims: Exaggerated hepatic glucose production is one of the hallmarks of type 2 diabetes. Sulforaphane (SFN) has been suggested as a new potential anti-diabetic compound. However, the effects of SFN in hepatocytes are yet unclear. Accumulating evidence points to the close structural contacts between the ER and mitochondria, known as mitochondria-associated ER membranes (MAMs), as important hubs for hepatic metabolism. We wanted to investigate whether SFN could affect hepatic glucose production and MAMs. Materials and methods: We used proximity ligation assays, analysis of ER stress markers and glucose production assays in hepatoma cell lines, primary mouse hepatocytes and diabetic animal models. Results: SFN counteracted the increase of glucose production in palmitate-treated mouse hepatocytes. SFN also counteracted palmitate-induced MAM disruptions. Moreover, SFN decreased the ER stress markers CHOP and Grp78. In ob/ob mice, SFN improved glucose tolerance and reduced exaggerated glucose production. In livers of these mice, SFN increased MAM protein content, restored impaired VDAC1-IP3R1 interactions and reduced ER stress markers. In mice on HFHSD, SFN improved glucose tolerance, MAM protein content and ER-mitochondria interactions to a similar extent to that of metformin. Conclusions: The present findings show that MAMs are severely reduced in animal models of glucose intolerance, which reinforces the role of MAMs as a hub for insulin signaling in the liver. We also show that SFN restores MAMs and improves glucose tolerance by a similar magnitude to that of metformin. These data highlight SFN as a new potential anti-diabetic compound. (C) 2017 Elsevier B.V. All rights reserved.

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