Structural requirements for the cytoprotective actions of mono‐unsaturated fatty acids in the pancreatic β‐cell line, BRIN‐BD11

Abstract

Background and purpose: Exposure of pancreatic b-cells to long-chain free fatty acids leads to differential responses according to the chain length and degree of unsaturation. In particular, long-chain saturated molecules such as palmitate (C16:0) cause apoptosis, whereas equivalent mono-unsaturated species (for example, palmitoleate (C16:1)) are not overtly toxic. Moreover, mono-unsaturates exert a powerful cytoprotective response against a range of proapoptotic stimuli. However, the structural requirements that determine cytoprotection have not been determined and form the basis of the present study. Experimental approach: BRIN-BD11 and INS-1 b-cells were exposed either to the saturated fatty acid palmitate, or to serum withdrawal, to mediate cytotoxicity. The protective effects of a wide range of mono-unsaturated fatty acid derivatives were tested in cytotoxicity assays. Effector caspase activity was also measured and correlated with viability. Key results: The cytotoxic actions of palmitate were inhibited dose-dependently by long-chain mono-unsaturated fatty acids with a defined potency order C18:14C16:1cC14:1. The configuration of the double bond was also important with cis forms being more potent than trans forms. Alkylated mono-unsaturated fatty-acid derivates were also cytoprotective, although their efficacy declined as the alkyl chain length increased. Cytoprotection was achieved rapidly on addition of mono-unsaturates and correlated with a rapid and dramatic inhibition of caspase-3/7 activity in palmitate-treated cells. Conclusions and implications:The data reveal the structural requirements that dictate the cytoprotective actions of monounsaturated fatty acids in pancreatic b-cells. Metabolic activation is not required and the data point at the potential involvement of a fatty acid receptor in mediating cytoprotection.

Differential regulation of the endoplasmic reticulum stress response in pancreatic β-cells exposed to long-chain saturated and monounsaturated fatty acids

“…However, the situation is complex since studies with isolated human islets, primary rat b-cells and various b-cell lines have demonstrated that certain long-chain saturated fatty acids have the greatest propensity to induce cytotoxicity, while shorter chain saturated molecules (!C14) and long-chain unsaturated species are much less damaging. Indeed, some unsaturated fatty acids are potently cytoprotective and can attenuate the loss of viability caused by their saturated counterparts (Maedler et al 2003, Welters et al 2004, Diakogiannaki et al 2007, Dhayal et al 2008. This implies that fatty acids exert differential effects according to their chain length and degree of unsaturation but the mechanisms that underlie these differences have not been defined.…”

“…This concept is important since it has emerged that b-cell lipotoxicity results from the activation of specific proapoptotic pathways that are differentially regulated by saturated and monounsaturated molecules. Thus, while long-chain saturated fatty acids such as palmitate (C16:0) and stearate (C18:0) are powerfully lipotoxic to pancreatic b-cells, the equivalent monounsaturated molecules (palmitoleate (C16:1) and oleate (C18:1)) are potently cytoprotective under in vitro conditions (Welters et al 2004, Diakogiannaki et al 2007, Dhayal et al 2008. In the present work, we have investigated the possibility that this may reflect a differential activation of the integrated stress response by saturated and monounsaturated fatty acids.…”

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…For example, GPR40 is known to be activated by both saturated and unsaturated fatty acids but only the latter are cytoprotective [75]. Furthermore, methylated fatty acids do not activate GPR40 whereas they are equipotent with underivatised molecules Page 11 of 34 A c c e p t e d M a n u s c r i p t as mediators of cytoprotection [76]. On this basis, it seems unlikely that GPR40 plays a major role in protecting β-cells against toxic insults.…”

“…However, firm evidence to support this hypothesis is entirely lacking. Indeed, the demonstration that methyl-esters of unsaturated fatty acids are extremely potent cytoprotective agents in the β-cell [146] argues against this possibility since these fatty acids do not activate GPR120. Thus, at present its role in β-cells remains enigmatic.…”

Phytochemical analysis of picea abies bark obtained by accelerated solventextraction

“…These compounds have been reported for several biological activities such as antioxidant, antitumor, cytotoxic, antimitotic (González et al, 2010), antibacterial (Gu& Wang, 2010, cytoprotective (Dhayal et al, 2008), anti-inflammatory (Hua et al, 2006) and so on.…”