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Insulin demand regulates ? cell number via the unfolded protein response.

ABSTRACT: Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic ? cell number expands in response to an increase in insulin demand. Lineage tracing shows that new ? cells are generated from proliferation of mature, differentiated ? cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the ? cell unfolded protein response (UPR), which senses insulin production, as a regulator of ? cell proliferation. Using genetic and physiologic models, we determined that among the population of ? cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand-induced ? cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human ? cells, suggesting that therapeutic UPR modulation has potential to expand ? cell mass in people at risk for diabetes. Together, this work defines a stem cell-independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.

SUBMITTER: Sharma RB

PROVIDER: S-EPMC4607122 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Insulin demand regulates β cell number via the unfolded protein response.

Sharma Rohit B RB O'Donnell Amy C AC Stamateris Rachel E RE Ha Binh B McCloskey Karen M KM Reynolds Paul R PR Arvan Peter P Alonso Laura C LC

The Journal of clinical investigation 20150921 10

Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic β cell number expands in response to an increase in insulin demand. Lineage tracing shows that new β cells are generated from proliferation of mature, differentiated β cells; however, the mechanism by which these mature ce ...[more]

PMID: 26389675

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Project description:BackgroundMitochondrial quality control (MQC) plays a critical role in the progression of tubulointerstitial injury in diabetic kidney disease (DKD). The mitochondrial unfolded protein response (UPRmt), which is an important MQC process, is activated to maintain mitochondrial protein homeostasis in response to mitochondrial stress. Activating transcription factor 5 (ATF5) is critical in the mammalian UPRmt via mitochondria-nuclear translocation. However, the role of ATF5 and UPRmt in tubular injury under DKD conditions is unknown.MethodsATF5 and UPRmt-related proteins including heat shock protein 60 (HSP60) and Lon peptidase 1 (LONP1), in DKD patients and db/db mice were examined by immunohistochemistry (IHC) and western blot analysis. Eight-week-old db/db mice were injected with ATF5-shRNA lentiviruses via the tail vein, and a negative lentivirus was used as a control. The mice were euthanized at 12 weeks, and dihydroethidium (DHE) and TdT-mediated dUTP nick end labeling (TUNEL) assays were performed to evaluate reactive oxygen species (ROS) production and apoptosis in kidney sections, respectively. In vitro, ATF5-siRNA, ATF5 overexpression plasmids or HSP60-siRNA were transfected into HK-2 cells to evaluate the effect of ATF5 and HSP60 on tubular injury under ambient hyperglycemic conditions. Mitochondrial superoxide (MitoSOX) staining was used to gauge mitochondrial oxidative stress levels, and the early stage of cell apoptosis was examined by Annexin V-FITC kits.ResultsIncreased ATF5, HSP60 and LONP1 expression was observed in the kidney tissue of DKD patients and db/db mice and was tightly correlated with tubular damage. The inhibition of HSP60 and LONP1, improvements in serum creatinine, tubulointerstitial fibrosis and apoptosis were observed in db/db mice treated with lentiviruses carrying ATF5 shRNA. In vitro, the expression of ATF5 was increased in HK-2 cells exposed to high glucose (HG) in a time-dependent manner, which was accompanied by the overexpression of HSP60, fibronectin (FN) and cleaved-caspase3 (C-CAS3). ATF5-siRNA transfection inhibited the expression of HSP60 and LONP1, which was accompanied by reduced oxidative stress and apoptosis in HK-2 cells exposed to sustained exogenous high glucose. ATF5 overexpression exacerbated these impairments. HSP60-siRNA transfection blocked the effect of ATF5 on HK-2 cells exposed to continuous HG treatment. Interestingly, ATF5 inhibition exacerbated mitochondrial ROS levels and apoptosis in HK-2 cells in the early period of HG intervention (6 h).ConclusionsATF5 could exert a protective effect in a very early stage but promoted tubulointerstitial injury by regulating HSP60 and the UPRmt pathway under DKD conditions, providing a potential target for the prevention of DKD progression.

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Insulin demand regulates ? cell number via the unfolded protein response.

Publications

Insulin demand regulates β cell number via the unfolded protein response.

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