Journal article
Lipase Maturation Factor 1 (Lmf1) Is Induced by Endoplasmic Reticulum Stress Through Activating Transcription Factor 6α (Atf6α) Signaling
The Journal of biological chemistry, Vol.289(35), pp.24417-24427
08/2014
DOI: 10.1074/jbc.M114.588764
PMCID: PMC4148868
PMID: 25035425
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.
Details
- Title: Subtitle
- Lipase Maturation Factor 1 (Lmf1) Is Induced by Endoplasmic Reticulum Stress Through Activating Transcription Factor 6α (Atf6α) Signaling
- Creators
- Hui Z Mao - Medical Genetics Research Institute and Cedars-Sinai Medical Center, Los Angeles, California 90048Nicole Ehrhardt - Medical Genetics Research Institute and Cedars-Sinai Medical Center, Los Angeles, California 90048Candy Bedoya - Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048Javier A Gomez - Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Diane DeZwaan-McCabe - Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Imran N Mungrue - Department of Pharmacology and Experimental Therapeutics, Louisiana State University School of Medicine, New Orleans, Louisiana 70112Randal J Kaufman - Degenerative Disease Research, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, andD. Thomas Rutkowski - Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Miklós Péterfy - Medical Genetics Research Institute and Cedars-Sinai Medical Center, Los Angeles, California 90048
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.289(35), pp.24417-24427
- DOI
- 10.1074/jbc.M114.588764
- PMID
- 25035425
- PMCID
- PMC4148868
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: HL094709, DK084058, DK088227, DK042394, HL052173, HL28481
- Language
- English
- Date published
- 08/2014
- Academic Unit
- Anatomy and Cell Biology; Internal Medicine
- Record Identifier
- 9984094508402771
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