Modulation of Lipid‐Induced ER Stress by Fatty Acid Shape

Abstract

Exposure of pancreatic β cells to long-chain saturated fatty acids (SFA) induces a so-called endoplasmic reticulum (ER) stress that can ultimately lead to cell death. This process is believed to participate in insulin deficiency associated with type 2 diabetes, via a decrease in β-cell mass. By contrast, some unsaturated fatty acid species appear less toxic to the cells and can even alleviate SFA-induced ER stress. In the present study, we took advantage of a simple yeast-based model, which brings together most of the trademarks of lipotoxicity in human cells, to screen fatty acids of various structures for their capacity to counter ER stress. Here we demonstrate that the tendency of a free fatty acid (FFA) to reduce SFA toxicity depends on a complex conjunction of parameters, including chain length, level of unsaturation, position of the double bonds and nature of the isomers (cis or trans). Interestingly, potent FFA act as building blocks for phospholipid synthesis and help to restore an optimal membrane organization, compatible with ER function and normal protein trafficking.

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

“…Indeed, when the levels of cholesterol and/or saturated phospholipid accidently increase, this promotes a stress characterized by the accumulation of unfolded transmembrane proteins. In turn, this stress triggers a response characterized by the upregulation of a fatty acid desaturase (Ole1 in yeast) and the arrest of cholesterol synthesis [9][10][11][12] . In addition, several peripheral proteins involved in various functions (lipid transfer, autophagy, nuclear pore formation, vesicle tethering and protein coat dynamics) seem to recognize lipid-packing defects by adsorbing preferentially to positively curved membranes through the insertion of long amphipathic sequences 4,[13][14][15][16][17] .…”

Targeting surface voids to counter membrane disorders in lipointoxication-related diseases

“…Based on our previous work, 64 fatty acids of various chain length and levels of unsaturation were first tested (Table S1). Interestingly, in contrast to Ole, among the 12 UFAs which had proven to be efficient in countering SFA toxicity in the hem1Δ model (Deguil et al, 2011), nine appeared to be less toxic to the quadruple mutant cells than Ole (Table S1). However, it appeared that low toxicity systematically correlated with a lower efficiency to counter the SFA-deleterious effects on growth (compare Ole and cis-vaccenic acid, for example).…”

“…As a consequence, the hem1Δ cells stop growing as early as 5 h after a shift to non-δ-ALA supplemented medium [YPD+ergosterol (Erg), denoted Ø] and this arrest correlates with an accumulation of SFA [mainly myristic (C14:0), palmitic (C16:0) and stearic (C18:0) acids] at the expense of unsaturated fatty acids [UFAs; palmitoleic (C16:1) and oleic (C18:1) acids] (Ferreira et al, 2004;Pineau et al, 2008). Interestingly, cell growth can be fully recovered and all the trademarks of SFA lipointoxication alleviated if selective UFAs, such as the mono-unsaturated fatty acid oleic acid (Ole), are added to the medium [ (Deguil et al, 2011); Table S1 and Fig. 1A].…”

“…Because it has been shown that the essential features required to promote viability reflects the ability of fatty acids to alleviate ER stress both in yeast and mammalian cells (Deguil et al, 2011;Dhayal and Morgan, 2011;Pineau et al, 2009), the capacity of OAG and OLPA to counteract the SFA-related UPR-induction was tested (Fig. 2).…”

“…The fatty acyl content of a phospholipid molecule contributes to its overall shape, which is defined by the cross-sectional area of the headgroup relative to the cross-sectional area of its acyl chains (de Kroon, 2007). For example, an oleoyl chain (C18:1) occupies a larger volume than a palmitoyl chain (C16:0), because the double bond induces a 'kink' in the middle of the chain (Deguil et al, 2011). Therefore, inserting a kinked acyl chain within a phospholipid species tends to shift its shape from rather cylindrical to conical.…”