Cidea is associated with lipid droplets and insulin sensitivity in humans

Puri, Vishwajeet; Ranjit, Srijana; Konda, Silvana; Nicoloro, Sarah M.; Straubhaar, Juerg R.; Chawla, Anil; Chouinard, My T.; Lin, Chen-Yi; Burkart, Alison; Corvera, Silvia; Perugini, Richard A.; Czech, Michael P.

doi:10.1073/pnas.0802063105

Cited by 329 publications

(378 citation statements)

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“…Consistent with this observation, Cidec knockdown using RNA interference significantly stimulates lipolysis and results in the fragmentation of large storage lipid droplets to multiple small ones (Puri et al, 2007). Like perilipin, both Cidea and Cidec are regulated by PPARγ (Puri et al, 2008), and it is possible that the CIDE family proteins, similar to the PAT members, may play multiple roles in the formation of macrophage-derived foam cells.…”

Section: Cide Proteinsmentioning

confidence: 58%

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

2012

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Section: Cide Proteinsmentioning

confidence: 58%

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

2012

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“…Our gene-profiling analysis revealed that the expression of a number of lipogenic genes was significantly reduced in the liver of ROR␣ sg/sg mice. These included Cidec and Cidea, which regulate triglyceride storage, the size of lipid droplets, and lipolysis and which have been reported to be highly induced in hepatic steatosis (17,39,41). In addition, the expression of several genes implicated in the main pathway of triglyceride synthesis (37), including glycerol-3-phosphate acyltransferase (Gpam or Gpat1) and acyl-glycerol-3-phosphate acyltransferase 9 (Agpat9), and Mogat1, which is part of an alternative, less-studied pathway of triglyceride synthesis, was significantly reduced in liver of ROR␣ sg/sg mice.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Kang¹,

Okamoto²,

Takeda³

et al. 2011

Physiological Genomics

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AM. Transcriptional profiling reveals a role for ROR␣ in regulating gene expression in obesity-associated inflammation and hepatic steatosis. Physiol Genomics 43: 818 -828, 2011. First published May 3, 2011 doi:10.1152/physiolgenomics.00206.2010.-Retinoid-related orphan receptor (ROR)␣4 is the major ROR␣ isoform expressed in adipose tissues and liver. In this study we demonstrate that ROR␣-deficient staggerer mice (ROR␣ sg/sg ) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of ROR␣ sg/sg mice. In contrast, overexpression of ROR␣ in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in ROR␣ sg/sg liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by ROR␣. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of ROR␣ sg/sg mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in ROR␣ sg/sg WAT. Moreover, ROR␣ sg/sg mice fed with an HFD were protected from the development of insulin resistance. ROR␣ sg/sg mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that ROR␣ plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, ROR␣ may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. staggerer mice; obesity; metabolic syndrome; macrophage; insulinresistance; diabetes; retinoid-related orphan receptors OBESITY IS A MAJOR GLOBAL health concern. In the United States alone, 30% of the general population is obese and an estimated 66% of all adults are overweight (40). Obesity is associated with an elevated risk of several pathologies, including Type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancer, and airway disease (18,36). The molecular links between obesity and these diseases are beginning to be understood. It is now well recognized that obesity is associated with chronic low-grade inflammation and that inflammatory processes play an important role in obesity and related pathologies (18,44,53). Infiltration of macrophages and various T-lymphocytes in hypertrophic adipose tissues have been considered as important early events in the development of obesity-associated complications (14, 38, 57) and the release of proinflammatory cytokines by adipose tissue plays a key ...

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“…FSP27 transcript is expressed in both human and murine white adipocytes (13,25) and is present at lower levels in murine brown adipocytes (13). In mice, CIDEA is found only in brown adipocytes (13,44), whereas in humans a high level of CIDEA is noted in white adipocytes (26). CIDEB transcript is markedly enriched in human and murine liver, with expression also reported for murine kidney and intestine (11,13,15).…”

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confidence: 88%

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

Liu

Zhou

Kim

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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MS, Smas CM.Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA. Am J Physiol Endocrinol Metab 297: E1395-E1413, 2009. First published October 20, 2009 doi:10.1152/ajpendo.00188.2009.-The adipocytespecific protein FSP27, also known as CIDEC, is one of three cell death-inducing DFF45-like effector (CIDE) proteins. The first known function for CIDEs was promotion of apoptosis upon ectopic expression in mammalian cells. Recent studies in endogenous settings demonstrated key roles for CIDEs in energy metabolism. FSP27 is a lipid droplet-associated protein whose heterologous expression enhances formation of enlarged lipid droplets and is required for unilocular lipid droplets typical of white adipocytes in vivo. Here, we delineate relationships between apoptotic function and lipid droplet localization of FSP27. We demonstrate that ectopic expression of FSP27 induces enlarged lipid droplets in multiple human cell lines, which is indicative that its mechanism involves ubiquitously present, rather than adipocyte-specific, cellular machinery. Furthermore, promotion of lipid droplet formation in HeLa cells via culture in exogenous oleic acid offsets FSP27-mediated apoptosis. Using transient cotransfections and analysis of lipid droplets in HeLa cells stably expressing FSP27, we show that FSP27 does not protect lipid droplets from action of ATGL lipase. Domain mapping with eGFP-FSP27 deletion constructs indicates that lipid droplet localization of FSP27 requires amino acids 174 -192 of its CIDE C domain. The apoptotic mechanism of FSP27, which we show involves caspase-9 and mitochondrial cytochrome c, also requires this 19-amino acid region. Interaction assays determine the FSP27 CIDE C domain complexes with CIDEA, and Western blot reveals that FSP27 protein levels are reduced by coexpression of CIDEA. Overall, our findings demonstrate the function of the FSP27 CIDE C domain and/or regions thereof for apoptosis, lipid droplet localization, and CIDEA interaction.fat-specific protein 27; cell death-inducing DFF45-like effector A; adipose OBESITY AND ITS RELATED COMORBIDITIES are approaching epidemic levels (1, 9). The development of new therapeutic inroads to treat these conditions would be greatly facilitated by a full understanding of lipid homeostasis (35,36). Lipotoxicity is a highly detrimental outcome of the obese state, leading to derangement of cell function and/or cell death in various tissues (34,35,37). White adipocytes present in white adipose tissue are the major site storage of excess energy in the form of triacylglycerol, contained within intracellular lipid droplets (7,38). Efficient storage of excess fatty acids within adipocyte lipid droplets also serves to protect other cells and tissues from their lipotoxic effects (7, 38). Lipid droplets are highly dynamic organelles consisting of a neutral lipid core, a phospholipid monolayer, and a large number of lipid droplet-associated proteins (7, 38). The role for the vast majority ...

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Cidea is associated with lipid droplets and insulin sensitivity in humans

Abstract: adipocyte ͉ Cide ͉ diabetes ͉ fat droplet ͉ fat metabolism

Cited by 329 publications

References 45 publications

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

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