Sulforaphane improves disrupted ER-mitochondria interactions and suppresses exaggerated hepatic glucose production
(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.
(Less)
- author
- Tubbs, Emily LU ; Axelsson, Annika S. LU ; Vial, Guillaume ; Wollheim, Claes B. LU ; Rieusset, Jennifer and Rosengren, Anders H. LU
- organization
- publishing date
- 2018
- 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
- pmid:28923347
- ISSN
- 0303-7207
- DOI
- 10.1016/j.mce.2017.09.016
- language
- English
- LU publication?
- yes
- id
- 3e631a49-e330-422a-a4ea-693a6ef58a72
- date added to LUP
- 2017-10-10 07:17:08
- date last changed
- 2024-01-14 06:56:41
@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}}, keywords = {{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/10.1016/j.mce.2017.09.016}}, doi = {{10.1016/j.mce.2017.09.016}}, volume = {{461}}, year = {{2018}}, }