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

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.
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https://www.hal.inserm.fr/inserm-03666162
Contributor : Guillaume Vial Connect in order to contact the contributor
Submitted on : Thursday, May 12, 2022 - 11:42:28 AM
Last modification on : Friday, June 17, 2022 - 4:15:25 PM

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Emily Tubbs, Annika Axelsson, Guillaume Vial, Claes Wollheim, Jennifer Rieusset, et al.. Sulforaphane improves disrupted ER-mitochondria interactions and suppresses exaggerated hepatic glucose production. Molecular and Cellular Endocrinology, Elsevier, 2018, 461, pp.205-214. ⟨10.1016/j.mce.2017.09.016⟩. ⟨inserm-03666162⟩

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