title: Lipase maturation factor 1 (lmf1) is induced by endoplasmic reticulum stress through activating transcription factor 6α (Atf6α) signaling.
abstract: 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 endoplasmic reticulum (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 and mouse liver, we identified the Atf6α arm of the unfolded protein response as being responsible for the up-regulation 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 an unfolded protein response 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.
authors.affiliation: From the Medical Genetics Research Institute and.
authors.forename: Hui Z
authors.initials: HZ
authors.lastname: Mao
authors.affiliation: From the Medical Genetics Research Institute and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ehrhardt
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048.
authors.forename: Candy
authors.initials: C
authors.lastname: Bedoya
authors.affiliation: Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Gomez
authors.affiliation: Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
authors.forename: Diane
authors.initials: D
authors.lastname: DeZwaan-McCabe
authors.affiliation: the Department of Pharmacology and Experimental Therapeutics, Louisiana State University School of Medicine, New Orleans, Louisiana 70112.
authors.forename: Imran N
authors.initials: IN
authors.lastname: Mungrue
authors.affiliation: Degenerative Disease Research, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, and.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
authors.forename: D Thomas
authors.initials: DT
authors.lastname: Rutkowski
authors.affiliation: From the Medical Genetics Research Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, the Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California 90095 mpeterfy@ucla.edu.
authors.forename: Miklós
authors.initials: M
authors.lastname: Péterfy
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; C546367:LMF1 protein, mouse; D008565:Membrane Proteins
keywords: Activating Transcription Factor 6; Chaperone; Endoplasmic Reticulum (ER); Endoplasmic Reticulum Stress (ER Stress); Lipase; Lipase Maturation Factor 1; Unfolded Protein Response (UPR)