A Human-Specific Role of Cell Death-Inducing DFFA (DNA Fragmentation Factor-α)-Like Effector A (CIDEA) in Adipocyte Lipolysis and Obesity

Nordström, Elisabet Arvidsson; Rydén, Mikael; Backlund, Emma C.; Dahlman, Ingrid; Kaaman, Maria; Blomqvist, Lennart; Cannon, Barbara; Nedergaard, Jan; Arner, Peter

doi:10.2337/diabetes.54.6.1726

Cited by 166 publications

(180 citation statements)

References 47 publications

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“…The differential expression of CIDE proteins in WAT and BAT could be important in cell-specific LD morphologies as in mice CIDEC is highly expressed in WAT and BAT and CIDEA is largely restricted to BAT [48]. However, the presence of CIDEA is not enough to induce a multilocular phenotype as in humans it is also expressed in WAT [49] remodelling cycle, with progressive reduction on the LD size, followed by the formation of new LDs, which are subjected to an enlargement process [48], likely to be CIDEtriggered. This futile cycle of TAG degradation and resynthesis implies the release of substantial amounts of heat that will constitute a UCP1-independent thermogenic system.…”

Section: Ld Enlargement In Brown White and Brite Adipocytesmentioning

confidence: 99%

Lipid droplet growth: regulation of a dynamic organelle

Barneda

Christian

2017

Current Opinion in Cell Biology

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Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in energy metabolism, membrane synthesis and provision of lipid-derived signaling molecules.Although small LDs are observed in all types of eukaryotic cells, it is adipocytes that present the widest range of sizes up to the massive unilocular droplet of a white adipocyte. Our knowledge of the proteins and associated processes that control LD dynamics is improving. The dynamic expression of LD-associated proteins is vital for controlling LD biology and is most apparent during adipocyte differentiation. Recent findings on the molecular mechanisms of lipid droplet enlargement reveal the importance of distinct functional groups of proteins and phospholipids.Highlights (max 5 points 85 characters each) Lipid droplet fusion involves major changes in the LD membrane components.Phosphatidic Acid is a key regulator of LD dynamics.Adipocyte differentiation invokes profound regulation of lipid droplet proteins.Transitions between white and BRITE adipocytes require lipid droplet remodelling.

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Section: Ld Enlargement In Brown White and Brite Adipocytesmentioning

confidence: 99%

Lipid droplet growth: regulation of a dynamic organelle

Barneda

Christian

2017

Current Opinion in Cell Biology

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“…4 It is therefore possible that genetic differences in the transcriptional regulation of this gene may be of importance for weight regulation and/or insulin sensitivity. A set of SNPs in the 5 0 flanking region of the CIDEA sequence were recently described and could putatively influence transcriptional regulation of CIDEA.…”

Section: Discussionmentioning

confidence: 99%

“…It is interesting to note that TNF-a has previously been shown to regulate CIDEA expression through the c-Jun N-terminal kinase (JNK). 4 JNK phosphorylates and activates homodimers or heterodimers of c-jun and/or c-fos proteins termed AP-1 which act as transcription factors binding to AP-1 regulatory elements in the promoter regions of several mammalian genes. 18 Although we could not detect any AP-1 consensus sequences in the human CIDEA promoter using MatInspector, another software (AliBaba 2.1, TRANSFAC) predicted one putative AP-1 site at position À270/À258.…”

Section: Discussionmentioning

confidence: 99%

“…4 CIDEA is downregulated in obese patients and CIDEA mRNA levels correlate inversely with markers for the metabolic syndrome in a manner that appears to be human-specific. 4 In a gene profiling study of subcutaneous white adipose tissue (WAT) in obese women following diet-induced weight reduction, CIDEA was the most upregulated gene, 5 indicating a role for CIDEA in body weight regulation. Moreover, a single nucleotide polymorphism (SNP) in exon 4 of CIDEA, C19787G-T, resulting in a V115F amino acid substitution, is associated with body mass index (BMI) in a Swedish cohort of both genders.…”

Section: Introductionmentioning

confidence: 94%

“…Although the molecular action of CIDEA in human adipocytes is not clear, in vitro studies in human adipocytes show that CIDEA inhibits basal lipolysis and TNF-a production in these cells. 4 Thus, CIDEA may regulate insulin sensitivity indirectly through effects on TNF-amediated adipocyte lipolysis.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the human CIDEA promoter in fat cells

et al. 2008

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Background: Cell death-inducing DFFA (DNA fragmentation factor-a)-like effector A (CIDEA) is a protein that regulates lipolysis in human adipocytes through cross-talk involving tumor necrosis factor-a (TNF-a). TNF-a downregulates CIDEA mRNA although it is unclear whether this is mediated through transcriptional or post-transcriptional mechanisms. CIDEA has important metabolic effects in human fat cells and genetic variations in the human CIDEA gene have been correlated to the development of obesity. However, little is known about the factors regulating CIDEA expression in human adipocytes. We set out to describe the transcriptional control of human CIDEA. Methods: A 1.1-kb genomic fragment upstream of the transcriptional start site (TSS) of human CIDEA was cloned and deletion fragments were generated. Transcriptional activity of the promoter was analyzed by luciferase reporter assays in in vitrodifferentiated human adipocytes. The effect of TNF-a was assessed in human adipocytes and murine 3T3-L1 cells transfected with deletion fragments of the CIDEA promoter. Protein-DNA interactions were analyzed by electrophoretic mobility shift assays (EMSA). Results: Basal transcriptional activity was found in a 97-bp region upstream of the TSS. We studied the effect of three common haplotypes in the promoter region but found no significant difference in transcriptional activity among them. Incubation of in vitro-differentiated human adipocytes as well as 3T3-L1 cells with TNF-a reduced the transcriptional activity of the human CIDEA promoter, demonstrating a direct effect on CIDEA transcription. EMSAs and mutational analysis indicated that this was mediated by a nuclear factor-kB (NF-kB) site at position À163/À151. Conclusion: We demonstrate that basal transcription of the human CIDEA gene is confined to the 97 first bases upstream of TSS and that TNF-a negatively regulates transcription of this gene, which at least in part involves NF-kB activation.

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CIDE proteins and their regulatory mechanisms in lipid droplet fusion and growth

Xu,

Li,

et al. 2024

FEBS Letters

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The cell death‐inducing DFF45‐like effector (CIDE) proteins, including Cidea, Cideb, and Cidec/Fsp27, regulate various aspects of lipid homeostasis, including lipid storage, lipolysis, and lipid secretion. This review focuses on the physiological roles of CIDE proteins based on studies on knockout mouse models and human patients bearing CIDE mutations. The primary cellular function of CIDE proteins is to localize to lipid droplets (LDs) and to control LD fusion and growth across different cell types. We propose a four‐step process of LD fusion, characterized by (a) the recruitment of CIDE proteins to the LD surface and CIDE movement, (b) the enrichment and condensate formation of CIDE proteins to form LD fusion plates at LD–LD contact sites, (c) lipid transfer through lipid‐permeable passageways within the fusion plates, and (d) the completion of LD fusion. Lastly, we outline CIDE‐interacting proteins as regulatory factors, as well as their contribution in LD fusion.

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A Human-Specific Role of Cell Death-Inducing DFFA (DNA Fragmentation Factor-α)-Like Effector A (CIDEA) in Adipocyte Lipolysis and Obesity

Cited by 166 publications

References 47 publications

Lipid droplet growth: regulation of a dynamic organelle

Lipid droplet growth: regulation of a dynamic organelle

Characterization of the human CIDEA promoter in fat cells

CIDE proteins and their regulatory mechanisms in lipid droplet fusion and growth

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