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

Mol Cell Endocrinol. 2018 Feb 5:461:205-214. doi: 10.1016/j.mce.2017.09.016. Epub 2017 Sep 18.

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.

Keywords: Mitochondria-associated ER membranes; Sulphoraphane; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Glucose / biosynthesis*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Intracellular Membranes / metabolism
  • Isothiocyanates / pharmacology*
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sulfoxides

Substances

  • Endoplasmic Reticulum Chaperone BiP
  • Hspa5 protein, mouse
  • Isothiocyanates
  • Sulfoxides
  • Proto-Oncogene Proteins c-akt
  • sulforaphane
  • Glucose