Lipid homeostasis is essential for a maximal ER stress response

Changes in lipid metabolism are associated with aging and age-related diseases, including proteopathies. The endoplasmic reticulum (ER) is uniquely a major hub for protein and lipid synthesis, making its function essential for both protein and lipid homeostasis. However, it is less clear how lipid metabolism and protein quality may impact each other. Here, we identified let-767, a putative hydroxysteroid dehydrogenase in Caenorhabditis elegans, as an essential gene for both lipid and ER protein homeostasis. Knockdown of let-767 reduces lipid stores, alters ER morphology in a lipid-dependent manner, and blocks induction of the Unfolded Protein Response of the ER (UPRER). Interestingly, a global reduction in lipogenic pathways restores UPRER induction in animals with reduced let-767. Specifically, we find that supplementation of 3-oxoacyl, the predicted metabolite directly upstream of let-767, is sufficient to block induction of the UPRER. This study highlights a novel interaction through which changes in lipid metabolism can alter a cell's response to protein-induced stress.

Automated summary

Changes in lipid metabolism are associated with aging and age-related diseases, including proteopathies. This study identified let-767 as an essential gene for both lipid and ER protein homeostasis in Caenorhabditis elegans. Knockdown of let-767 affects lipid stores, ER morphology, and the induction of the UPRER. A reduction in lipogenic pathways restores UPRER induction in animals with reduced let-767 by blocking the metabolite 3-oxoacyl.