Journal
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
Volume 57, Issue -, Pages 212-227Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jnutbio.2018.02.017
Keywords
Diabetes; Pancreatic beta-cells; Kaempferol; Lipophagy; ER stress; Insulin
Funding
- University Grant Commission, Government of India
- Department of Science and Technology, Government of India [SR/SO/HS-39/2009]
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Kaempferol, a natural flavonoid, has the beneficial effects of preserving pancreatic beta-cell mass and function, but its action on beta-cell lipid metabolism still remains elusive. Recently, autophagy has been reported to play a major role in lipid metabolism in various cell types, but its role in pancreatic beta-cell's lipid metabolism is rarely reported. Here, we investigated the role of kaempferol-induced autophagy in inhibition of lipid stores, ER stress and beta-cell dysfunction in palmitic acid-challenged RIN-5F cells and isolated pancreatic islets. The lipid-lowering effect of kaempferol was determined by Oil Red O staining, triglyceride assay, BODIPY labeling, RT-PCR and immunoblot analysis of PLIN2 (the lipid droplet coat protein) expression. Further, the involvement of AMPK/mTOR-mediated lipophagy was established by pharmacological and genetic inhibitors of autophagy and AMPK. The co-localization studies of lipid droplets with autophagosomes/lysosomes by BODIPY-MDC-LysoTracker co-staining, LC3/BODIPY labeling and LC3/PLIN2 double immunolabeling further strengthened the findings. Kaempferol treatment exhibited decreased lipid stores and increased co-localization of lipid droplets with autophagosomes and lysosomes in palmitic acid-challenged beta-cells. Moreover, inhibition of autophagy led to decreased co-localization and increased lipid droplets accumulation. Kaempferol-induced alleviation of ER stress and beta-cell dysfunctions was established by immunoblot analysis of CHOP-IO (a key mediator of cell death in response to ER stress) and insulin content/secretion analysis respectively. Together, these findings suggest that kaempferol prevents ectopic lipid accumulation and ER stress, thus restoring beta-cell function through AMPK-mediated lipophagy. The current data implies that kaempferol may be a potential therapeutic candidate to prevent obesity-linked diabetic complications. (C) 2018 Elsevier Inc. All rights reserved.
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