Lipase Maturation Factor 1 is Induced by Endoplasmic Reticulum Stress Through Atf6{alpha} Signaling [Gene Regulation]

July 17th, 2014 by Mao, H. Z., Ehrhardt, N., Bedoya, C., Gomez, J. A., DeZwaan-McCabe, D., Mungrue, I. N., Kaufman, R. J., Rutkowski, D. T., Peterfy, M.

Lipase maturation factor 1 (Lmf1) is a critical determinant of plasma lipid metabolism, as demonstrated by severe hypertriglyceridemia associated with its mutations in mice and human subjects. Lmf1 is a chaperone localized to the ER and required for the post-translational maturation and activation of several vascular lipases. Despite its importance in plasma lipid homeostasis, the regulation of Lmf1 remains unexplored. We report here that Lmf1 expression is induced by ER stress in various cell lines and in tunicamycin (TM)-injected mice. Using genetic deficiencies in mouse embryonic fibroblasts (MEFs) and mouse liver, we identified the Atf6α arm of the unfolded protein response (UPR) as being responsible for the upregulation of Lmf1 in ER stress. Experiments with luciferase reporter constructs indicated that ER stress activates the Lmf1 promoter through a GC-rich DNA sequence 264 bp upstream of the transcriptional start site. We demonstrated that Atf6α is sufficient to induce the Lmf1 promoter in the absence of ER stress and this effect is mediated by the TM-responsive cis-regulatory element. Conversely, Atf6α deficiency induced by genetic ablation or a dominant-negative form of Atf6α abolished TM-stimulation of the Lmf1 promoter. In conclusion, our results indicate that Lmf1 is a UPR target gene and Atf6α signaling is sufficient and necessary for activation of the Lmf1 promoter. Importantly, the induction of Lmf1 by ER stress appears to be a general phenomenon not restricted to lipase-expressing cells, which suggests a lipase-independent cellular role for this protein in ER homeostasis.