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The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic ?-cells, glycemic control and inflammation: In vitro and in vivo studies.

ABSTRACT: Studying rats fed high cholesterol diet and a pancreatic ?-cell line (Min6), we aimed to determine the mechanisms by which quercetin protects against cholesterol-induced pancreatic ?-cell dysfunction and impairments in glycemic control. Quercetin prevented the increase in total plasma cholesterol, but only partially prevented the high cholesterol diet-induced alterations in lipid profile. Quercetin prevented cholesterol-induced decreases in pancreatic ATP levels and mitochondrial bioenergetic dysfunction in Min6 cells, including decreases in mitochondrial membrane potentials and coupling efficiency in the mitochondrial respiration (basal and maximal oxygen consumption rate (OCR), ATP-linked OCR and reserve capacity). Quercetin protected against cholesterol-induced apoptosis of Min6 cells by inhibiting caspase-3 and -9 activation and cytochrome c release. Quercetin prevented the cholesterol-induced decrease in antioxidant defence enzymes from pancreas (cytosolic and mitochondrial homogenates) and Min6 cells and the cholesterol-induced increase of cellular and mitochondrial oxidative status and lipid peroxidation. Quercetin counteracted the cholesterol-induced activation of the NF?B pathway in the pancreas and Min6 cells, normalizing the expression of pro-inflammatory cytokines. Quercetin inhibited the cholesterol-induced decrease in sirtuin 1 expression in the pancreas and pancreatic ?-cells. Taken together, the anti-apoptotic, antioxidant and anti-inflammatory properties of quercetin, and its ability to protect and improve mitochondrial bioenergetic function are likely to contribute to its protective action against cholesterol-induced pancreatic ?-cell dysfunction, thereby preserving glucose-stimulated insulin secretion (GSIS) and glycemic control. Specifically, the improvement of ATP-linked OCR and the reserve capacity are important mechanisms for protection of quercetin. In addition, the inhibition of the NF?B pathway is an important mechanism for the protection of quercetin against cytokine mediated cholesterol-induced glycemic control impairment. In summary, our data highlight cellular, molecular and bioenergetic mechanisms underlying quercetin's protective effects on ?-cells in vitro and in vivo, and provide a scientifically tested foundation upon which quercetin can be developed as a nutraceutical to preserve ?-cell function.

SUBMITTER: Carrasco-Pozo C

PROVIDER: S-EPMC5011185 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic β-cells, glycemic control and inflammation: In vitro and in vivo studies.

Carrasco-Pozo Catalina C Tan Kah Ni KN Reyes-Farias Marjorie M De La Jara Nicole N Ngo Shyuan Thieu ST Garcia-Diaz Diego Fernando DF Llanos Paola P Cires Maria Jose MJ Borges Karin K

Redox biology 20160826

Studying rats fed high cholesterol diet and a pancreatic β-cell line (Min6), we aimed to determine the mechanisms by which quercetin protects against cholesterol-induced pancreatic β-cell dysfunction and impairments in glycemic control. Quercetin prevented the increase in total plasma cholesterol, but only partially prevented the high cholesterol diet-induced alterations in lipid profile. Quercetin prevented cholesterol-induced decreases in pancreatic ATP levels and mitochondrial bioenergetic dy ...[more]

PMID: 27591402

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Project description:Background and purposeHigh-altitude pulmonary oedema (HAPE) experienced under high-altitude conditions is attributed to mitochondrial redox distress. Hence, hypobaric hypoxia (HH)-induced alteration in expression of mitochondrial biogenesis and dynamics genes was determined in rat lung. Further, such alteration was correlated with expression of mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (mtOXPHOS) genes. The prophylactic effect of dexamethasone (DEX) in counteracting the HH-induced mitochondrial distress was used as control to understand adaptation to high-altitude exposure.Experimental approachRats pretreated with DEX were exposed to normobaric normoxia (NN) or HH. HH-induced injury was assessed as an increase in lung water content, tissue damage and oxidant generation. Mitochondrial number, mtDNA content and mtOXPHOS activities were measured to determine mitochondrial function. The expression of mitochondrial biogenesis, dynamics and mtOXPHOS genes was studied.Key resultsHH-induced lung injury was associated with decreased mitochondrial number, mtDNA content and mtOXPHOS activities. HH exposure decreased the nuclear gene oestrogen-related receptor-? (ERR?), which interacts with PPAR-? coactivator-1? (PGC-1?) in controlling mitochondrial metabolism. Consequently, mtOXPHOS transcripts are repressed under HH. Further, HH modulated mitochondrial dynamics by decreasing mitofusin 2 (Mfn2) and augmenting fission 1 (Fis1) and dynamin-related protein 1 (Drp1) expression. Nevertheless, DEX treatment under NN (i.e. adaptation to HH) did not affect mitochondrial biogenesis and dynamics, but increased mtOXPHOS transcripts. Further, mtOXPHOS activities increased together with reduced oxidant generation. Also, DEX pretreatment normalized ERR? along with mitochondrial dynamics genes and increased mtOXPHOS transcripts to elicit the mitochondrial function under HH.Conclusions and implicationsHH stress (HAPE)-mediated mitochondrial dysfunction is due to repressed ERR? and mtOXPHOS transcripts. Thus, ERR?-mediated protection of mitochondrial bioenergetics might be the likely candidate required for lung adaptation to HH.

Dataset Information

The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic ?-cells, glycemic control and inflammation: In vitro and in vivo studies.

Publications

The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic β-cells, glycemic control and inflammation: In vitro and in vivo studies.

Similar Datasets

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