Thrombospondin 1 protects pancreatic β-cells from lipotoxicity via the PERK–NRF2 pathway

Abstract

The failure of β-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional β-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in β-cell survival during lipotoxic stress in rat, mouse and human models. THBS1 acts from within the endoplasmic reticulum to activate PERK and NRF2 and induce a protective antioxidant defense response against palmitate. Prolonged palmitate exposure causes THBS1 degradation, oxidative stress, activation of JNK and upregulation of PUMA, culminating in β-cell death. These findings shed light on the mechanisms leading to β-cell failure during metabolic stress and point to THBS1 as an interesting therapeutic target to prevent oxidative stress in type 2 diabetes.

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

“…This raises the alternative possibility that the PKR-like endoplasmic reticulum kinase (PERK) initiating axis of UPR was specifically inactivated by TFG deficiency, despite the activating transcription factor-6 (ATF6) and inositol requiring enzyme 1 (IRE1) axes being activated. Nrf2 activation is suggested to be downstream from PERK 25 . However, as discussed above, Nrf2 is not activated instead being downregulated in TFG-deficient islets, again showing no activation of the PERK axis of the UPR under TFG-deficiency.…”

Pancreatic β-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF)

“…The multimeric Ca 2ϩ -binding glycoprotein thrombospondin 1 (THBS1) protects cardiomyocytes against ER stress via activation of ATF6 and downstream chaperones (12). We have shown recently that THBS1 protects human and rodent ␤-cells from palmitate-induced apoptosis (13). Different from cardiomyocytes, however, this takes place through activation of the ER stress transducer protein kinase R-like endoplasmic reticulum kinase (PERK) and the downstream transcription factor NRF2, increasing the ␤-cell capacity to withstand oxidative stress induced by saturated fatty acids (13).…”

“…Here we tested whether THBS1 is equally beneficial to rodent and human ␤-cells exposed to cytokines or chemically induced ER stress. THBS1 was clearly protective, but this was mediated by a different mechanism compared with protection against lipotoxic ␤-cell demise (13) or cardiomyopathy (12); namely, through induction of the mesencephalic astrocyte-derived neutrotrophic factor (MANF). This raises the intriguing possibility that the multifunctional protein THBS1 changes roles and/or partner affinities in a cell-or stress-specific manner, as suggested recently for other complex biological systems (14).…”

A post-translational balancing act: the good and the bad of SUMOylation in pancreatic islets

“…The capacity of beta cells to handle nitrosative and oxidative stress is regulated in part by nuclear factor erythroid 2-related factor 2 (NRF2) [28], a transcription factor that controls the expression of antioxidant genes (particularly those related to the glutathione pathway). Similar to beta cell UBC9, NRF2 expression in beta cells protects against iNOS-induced islet dysfunction and glucose intolerance [28], and against palmitate-induced oxidative stress [29]. He et al nicely link UBC9 and NRF2 by showing that SUMOylation regulates the nuclear localisation and stability of NRF2, likely by preventing its ubiquitin-mediated proteasomal degradation.…”

“…The ability of high glucose culture, presumably a state of oxidative stress, to upregulate SUMO transcripts and UBC9 protein hints that this could be a feed-forward mechanism [20]. Also, recent work has suggested that palmitate-induced oxidative stress transiently increases NRF2 protein levels [29], although it is not yet known whether this results from a SUMO-dependent stabilisation.…”