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

Abstract

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 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 NFκB 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 β-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 β-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 NFκB 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 β-cells in vitro and in vivo, and provide a scientifically tested foundation upon which quercetin can be developed as a nutraceutical to preserve β-cell function.

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

“…The mitochondrial transmembrane potential was analyzed using a JC-1 Kit (Beyotime, Shanghai, China) according to the manufacturer's protocol [25]. The cellular ATP levels were measured using a firefly luciferase-based ATP assay kit (Beyotime).…”

Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

“…After differentiation and treatment, the cells were changed to unbuffered XF Base Medium supplemented with 1 mM pyruvate, 2 mM glutamine and 10 mM glucose and incubated at 37 °C in a non-CO2 incubator for 1 h. Then, the OCR was measured by the Extracellular Flux Analyzer (Seahorse Bioscience, Massachusetts, USA) as previously described [38]. The data were analyzed using Wave and Report Generator software.…”

Quercetin Inhibits Cell Migration and Invasion in Human Osteosarcoma Cells

“…Quercetin exerts its anticancer effects by inducing cell cycle arrest, apoptosis, and differentiation and by suppressing MMP secretion [48]. Moreover, quercetin also reduces tumor cell adhesion, invasiveness, metastasis, and angiogenesis [49, 50]. Therefore, we aspired to evaluate the effects of quercetin on tumor migration and invasion.…”