Lipid‐Induced ER Stress: Synergistic Effects of Sterols and Saturated Fatty Acids

Abstract

Stress within the endoplasmic reticulum (ER) induces a coordinated response, namely the unfolded protein response (UPR), devoted to helping the ER cope with the accumulation of misfolded proteins. Failure of the UPR plays an important role in several human diseases. Recent studies report that intracellular accumulation of saturated fatty acids (SFAs) and cholesterol, seen in diseases of high incidence, such as obesity or atherosclerosis, results in ER stress. In the present study, we evaluated the effects of perturbations to lipid homeostasis on ER stress/UPR induction in the model eukaryote Saccharomyces cerevisiae. We show that SFA originating from either endogenous (preclusion of fatty acid desaturation) or exogenous (feeding with extracellular SFA) sources trigger ER stress and that ergosterol, the major sterol in yeast, acts synergistically with SFA in this process. This latter effect is connected to ergosterol accumulation within microsomal fractions from SFA-accumulating cells, which display highly saturated phospholipid content. Moreover, treating the cells with the molecular chaperone 4-phenyl butyrate abolishes UPR induction, suggesting that lipid-induced ER stress leads to an overload of misfolded protein that acts, in turn, as the molecular signal for induction of the UPR. The present data are discussed in the context of human diseases that involve lipid deregulation.

Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells

“…Figure 2b shows that reduction of lon protease expression did not induce ER stress. In contrast, treatment with cholesterol and palmitate, known inducers of ER stress, did trigger ER stress [18,19] (Fig. 2b).…”

Cancer Cell Dependence on Unsaturated Fatty Acids Implicates Stearoyl-CoA Desaturase as a Target for Cancer Therapy

“…Data have recently emerged showing that an excess of SFAs and cholesterol induces ER stress (27)(28)(29). In addition, Pineau and colleagues reported that ER stress induced by SFAs and sterols could be rescued by 4-phenyl butyrate, a molecular protein-folding chaperone (30). Furthermore, it has been shown that membrane sterols (which can themselves induce ER stress) inhibit protein translocation across the ER membrane (31).…”

Endoplasmic Reticulum Stress Promotes Macrophage-derived Foam Cell Formation by Up-regulating Cluster of Differentiation 36 (CD36) Expression

“…We (19) and others (26,27) have demonstrated that cholesterol accumulation in the ER membrane triggers ER stress and activation of the UPR in cultured macrophages. Accumulating evidence reveals that ER stress is a cross-point to link cellular processes with multiple risk factors that exist in all stages of AS (10) and believed to play a critical role in lipid metabolic disorder (28), activation of inflammatory reactions (29), and cellular apoptosis (30). Activation of ER stress pathways is also a characteristic of lipid-laden macrophages in both early and advanced atherosclerotic lesions and is proposed to play a role in plaque vulnerability and acute cardiac death (13,26,31), while reduction of ER stress in macrophages alleviates AS in mice (14,15).…”