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

Research output: Contribution to journalArticle

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.

Details

Authors
Organisations
External organisations
  • University of Geneva Medical School
  • University of Gothenburg
  • Claude Bernard University Lyon 1
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • Mitochondria-associated ER membranes, Sulphoraphane, Type 2 diabetes
Original languageEnglish
Pages (from-to)205-214
JournalMolecular and Cellular Endocrinology
Volume461
Early online date2017 Sep 18
StatePublished - 2018
Publication categoryResearch
Peer-reviewedYes