Distinct pathways of cholesterol biosynthesis impact on insulin secretion

Abstract

Results from previous investigations have indicated that glucose-stimulated insulin secretion (GSIS) is affected by changes in cholesterol and its intermediates, but the precise link between secretion and cholesterol has not been thoroughly investigated. In this study, we show the contribution of both protein isoprenylation and cholesterol-dependent plasma membrane structural integrity to insulin secretion in INS-1E cells and mouse islets. Acute (2 h) inhibition of hydroxyl-methylglutaryl-CoA reductase by simvastatin (SIM) resulted in inhibition of GSIS without reduction in total cellular cholesterol content. This effect was prevented by cell loading with the isoprenyl molecule geranylgeranyl pyrophosphate. Chronic (24 h) inhibition of cholesterol biosynthesis resulted in inhibition of GSIS with a significant reduction in total cellular cholesterol content, which was also observed after the inhibition of cholesterol biosynthesis downstream of isoprenoid formation. Electron paramagnetic resonance analyses of INS-1E cells showed that the SIM-induced reduction in cholesterol increased plasma membrane fluidity. Thus, the blockade of cholesterol biosynthesis resulted in the reduction of availability of isoprenoids, followed by a reduction in the total cholesterol content associated with an increase in plasma membrane fluidity. Herein, we show the different contributions of cholesterol biosynthesis to GSIS, and propose that isoprenoid molecules and cholesterol-dependent signaling are dual regulators of proper b-cell function.

Chronic Exposure to Proline Causes Aminoacidotoxicity and Impaired Beta-Cell Function: StudiesIn Vitro

“…A decrease in insulin secretion was observed under long-term inhibition of CH synthesis in insulin-secreting cells [23]. The associated impairment of GSIS is probably due to an effect of reduction in the protein isoprenylation and more importantly through membrane disarrangement [23]. Thus, both increase [24][25][26] and reduction [23] in β-cell CH content have been shown to reduce insulin secretion.…”

“…The associated impairment of GSIS is probably due to an effect of reduction in the protein isoprenylation and more importantly through membrane disarrangement [23]. Thus, both increase [24][25][26] and reduction [23] in β-cell CH content have been shown to reduce insulin secretion. In conclusion, a critical concentration of cellular/membrane CH content is required for adequate secretion of insulin.…”

The role of endosomal cholesterol trafficking protein, StAR-related lipid transfer domain 3 (StarD3/MLN64), in BRIN-BD11 insulinoma cells

“…Inhibition of cellular biosynthesis by ‘statin’ drugs, or depletion of plasma membrane cholesterol by methyl-β-cyclodextrin (MCD), reduce glucose-stimulated insulin secretion (GSIS) and content in β-cells and islets; statin treatment also causes delayed ATP production, inflammation and β-cell apoptosis (Tscuhiya et al, 2010; Zuniga-Hertz et al, 2015). Paradoxically, accumulation of β-cell/islet cholesterol caused by low density lipoprotein (LDL) receptor deficiency (Souza et al, 2013) or loss of ATP binding cassette transporters (ABCA1, ABCG1) which efflux cholesterol to apolipoprotein A-I (apo A-I) and high density lipoprotein (HDL) (Kruit et al, 2012), is also associated with loss of GSIS, impaired calcium handling, increased reactive oxygen species (ROS), inflammation and apoptosis.…”

Protein prenylation in islet β-cell function in health and diabetes: Putting the pieces of the puzzle together

“…2), a signaling step downstream to Fpp biosynthesis, inhibited cholesterol biosynthesis as well as GSIS. Based on these findings the authors concluded that protein prenylation and cholesterol biosynthetic pathways represent dual signaling mechanisms involved in GSIS [22]. Together, these findings provided additional clues with regard to regulatory roles of MVA-derived intermediates in GSIS.…”

“…Recent investigations by Zuniga-Hertz and associates have suggested additional roles for events in cellular cholesterol metabolic pathway in GSIS from INS-1E cells and mouse islets [22]. They observed a significant reduction in GSIS by simvastatin under acute conditions (2 h exposure).…”