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

Tubbs, Emily LU ; Axelsson, Annika S. LU ; Vial, Guillaume; Wollheim, Claes B. LU ; Rieusset, Jennifer and Rosengren, Anders H. LU (2018) In Molecular and Cellular Endocrinology 461. p.205-214
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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Mitochondria-associated ER membranes, Sulphoraphane, Type 2 diabetes
in
Molecular and Cellular Endocrinology
volume
461
pages
205 - 214
publisher
Elsevier
external identifiers
  • scopus:85029670824
ISSN
0303-7207
DOI
language
English
LU publication?
yes
id
3e631a49-e330-422a-a4ea-693a6ef58a72
date added to LUP
2017-10-10 07:17:08
date last changed
2018-05-29 09:33:45
@article{3e631a49-e330-422a-a4ea-693a6ef58a72,
  abstract     = {<p>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.</p>},
  author       = {Tubbs, Emily and Axelsson, Annika S. and Vial, Guillaume and Wollheim, Claes B. and Rieusset, Jennifer and Rosengren, Anders H.},
  issn         = {0303-7207},
  keyword      = {Mitochondria-associated ER membranes,Sulphoraphane,Type 2 diabetes},
  language     = {eng},
  pages        = {205--214},
  publisher    = {Elsevier},
  series       = {Molecular and Cellular Endocrinology},
  title        = {Sulforaphane improves disrupted ER-mitochondria interactions and suppresses exaggerated hepatic glucose production},
  url          = {http://dx.doi.org/},
  volume       = {461},
  year         = {2018},
}