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CIDE proteins and metabolic disorders

Gong, Jingyi; Sun, Zhiqi; Li, Peng

Current Opinion in Lipidology: April 2009 - Volume 20 - Issue 2 - p 121–126
doi: 10.1097/MOL.0b013e328328d0bb
Genetics and molecular biology: Edited by Jose M. Ordovas and E. Shyong Tai
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Purpose of review The cell death-inducing DFF45-like effector (CIDE) family proteins, comprising three members, Cidea, Cideb, and Fsp27 (Cidec), have emerged as important regulators for various aspects of metabolism. This review summarizes our current understanding about the physiological roles of CIDE proteins, their transcriptional regulations, and their underlying mechanism in controlling the development of metabolic disorders.

Recent findings Animals with deficiency in Cidea, Cideb, and Fsp27 all display lean phenotypes with higher energy expenditure and are resistant to diet-induced obesity and insulin resistance. CIDE proteins, localized to lipid droplets and endoplasmic reticulum, control lipid metabolism in adipocytes and hepatocytes through regulating AMP-activated protein kinase stability and influencing lipogenesis or lipid droplet formation. The expression of CIDE proteins is controlled at both transcriptional and posttranslational levels and positively correlates with the development of obesity, liver steatosis, and insulin sensitivity in both rodents and humans.

Summary CIDE proteins are important regulators of energy homeostasis and are closely linked to the development of metabolic disorders including obesity, diabetes, and liver steatosis. They may serve as potential molecular targets for the screening of therapeutic drugs for these diseases.

Protein Science Laboratory of Ministry of Education, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China

Correspondence to Dr Peng Li, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China Tel/fax: +86 10 62797121; e-mail: li-peng@mail.tsinghua.edu.cn

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Introduction

Metabolic disorders including obesity, hyperlipidemia, insulin resistance, liver steatosis, and hypertension are a group of diseases associated with metabolic malfunction and unbalanced energy homeostasis. The cell death-inducing DFF45-like effector (CIDE) proteins, Cidea, Cideb and Fsp27, are predominantly expressed in brown adipose tissue (BAT), liver and white adipose tissues (WATs). Studies using animals deficient in CIDE proteins have demonstrated that this class of proteins plays important roles in lipid storage, lipid droplet formation, lipolysis and the development of obesity, diabetes, and liver steatosis. Here we summarize recent findings on the CIDE proteins, with particular emphasis on their molecular mechanisms in controlling energy homeostasis.

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Tissue distribution and transcriptional regulation of CIDE proteins

CIDE proteins contain an evolutionary conserved CIDE-N domain that shares homology to the DNA fragment factor 40/45 (DFF40/45) [1] and a CIDE-C domain that is unique among CIDE proteins [2]. Unlike DFF40/45 proteins that are ubiquitously expressed, CIDE family proteins have distinct tissue expression patterns with Cidea in BAT in rodents [3], Cideb [4••] in liver, and Fsp27 in WAT and BAT [3,5••,6••]. Cidea mRNA is detected in human WAT tissues, which might reflect a heterogeneous nature of human WAT [7]. Interestingly, mRNAs of Fsp27 and Cidea were also detected in fatty livers in which excess amount of lipid is accumulated and large lipid droplets are formed [8–10].

CIDE proteins are subjected to tight regulation on both transcriptional and posttranslational levels. Fsp27 is expressed in differentiated white adipocytes [5••,11,12] and controlled by transcription factors CCAAT/enhancer binding protein (C/EBP) and peroxisome proliferator-activated receptor (PPARγ) [8,11]. TNF-α, a negative regulator of C/EBP, reduced the Fsp27 gene expression [13]. Cidec, a human homolog of rodent Fsp27, is induced by PPARγ2 [14]. Retinoid X receptor (RXR) also binds to the Fsp27 promoter region in a PPARγ γ-dependent manner [15]. In liver, Fsp27 is a direct target of PPARγ [9]. Cidea promoter region contains both PPARα and PPARγ response elements and can be activated by PPAR agonist [10]. In addition, PGC-1α can activate Cidea expression through binding to estrogen-related receptor alpha (ERRα) and nuclear respiratory factor-1 (NRF-1), while RIP140, a corepressor of nuclear receptors, interacts with PGC-1α and represses its transcriptional activity on Cidea promoter [16,17]. Investigation in tumor cells indicates that CpG methylation on the Cidea promoter region may play a crucial role in establishing and maintaining tissue-specific and cell-specific Cidea expression [18]. TNF-α negatively regulates transcription of Cidea through NF-κB activation [19]. The expression of human Cideb is regulated by upstream and internal promoters. While CpG methylation in the upstream promoter region controls the production of longer transcript, hepatocyte nuclear factor-4α (HNF4α) binds to the internal promoter and controls the production of shorter transcripts of Cideb [20].

On the posttranslational level, Cidea is degraded through ubiquitin-mediated proteasome pathway in adipocytes [21]. Furthermore, Cidea was shown to be modified by O-linked glycosylation that may control its subcellular localization and cell death-inducing activity [22]. However, it remains to be determined if Cideb and Fsp27 are controlled by similar posttranslational modifications.

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Subcellular localization of CIDE proteins

Much effort has been made toward subcellular localization of the CIDE proteins. When overexpressed in heterologous cells, Cidea and Cideb proteins showed a distribution pattern similar to that of mitochondria specific marker – mitotracker [3,23]. Later, it was discovered that this particular pattern was associated specifically with the later stage of cell death. Recently, Cidea was found to be localized to endoplasmic reticulum (ER) [24••] and lipid droplet [25•]. Similarly, Fsp27 targets to lipid droplets in adipocytes [5••,26,27••,28]. Lipid droplets are highly dynamic organelles that are in close contact with multiple subcellular structures including ER, endosomes, mitochondria, and plasma membrane [29]. Therefore, the discrepancy of these observations might be due to the overexpression of proteins in heterologous cells that undergo specific morphological changes during apoptosis or the diverse localization of lipid droplets. As nascent lipid droplet was proposed to be derived from the cytosolic leaflet of ER [30], the ER and lipid droplet localization of CIDE family proteins indicate their important functions in lipid droplet formation.

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CIDE proteins and the development of metabolic disorders

Due to their sequence homology to DFF40/45, early studies on CIDE family proteins mainly focused on their cell death-inducing activity. Cideb proteins could form dimers through the N-terminal [31] or C-terminal region, and ectopic expression of Cideb induces caspase-independent cell death in a dimer-dependent manner [23]. Cideb expression was also correlated with neuronal apoptosis after nerve injury [32]. Furthermore, Cideb was shown to interact with NS2, a nonstructural protein encoded by HCV, which inhibits Cideb-induced cell death [33]. Furthermore, Cidea could regulate apoptosis induced by TGF-β pathway in human breast epithelial cells [22]. In addition, Fsp27 and Cidec were reported to play a role in cell death and tumorigenesis [34,35].

We generated Cidea-deficient mice and observed no obvious difference in cell death between wild-type and Cidea−/− brown adipocytes. Surprisingly, Cidea−/− mice showed a drastic lean phenotype with lower adiposity, decreased leptin and plasma lipid levels and are resistant to diet-induced obesity. In particular, lipid content in Cidea−/− mice is dramatically reduced upon cold treatment, suggesting that Cidea is important in controlling energy expenditure in adipose tissues. In addition, Cidea−/− mice have higher glucose disposition rate and improved insulin sensitivity. The lean phenotype of Cidea-null mice may be due to increased whole body metabolism, higher basal lipolysis, and fatty acid oxidation in their brown adipocytes [36] (Table 1, Fig. 1).

Table 1

Table 1

Figure 1

Figure 1

The role of CIDE proteins in regulating metabolic disorders was further confirmed in Cideb−/− mice. Deficiency of Cideb resulted in lower plasma triacylglycerol (TAG) and fatty acid levels, decreased white fat mass and increased whole body metabolism, and a lean phenotype [4••,36]. In addition, Cideb−/− mice are resistant to diet-induced obesity and liver steatosis. More interestingly, Cideb−/− mice showed decreased plasma insulin concentration, increased hepatic insulin sensitivity manifested by increased IRS-1 and AKT2 phosphorylation in response to insulin stimulation. The lean phenotype of Cideb−/− mice is likely due to a combination of increased fatty acid oxidation and decreased lipogenesis in Cideb−/− hepatocytes. Consistently, SREBP-1c, a crucial factor in regulating fatty acid synthesis, was significantly downregulated, resulting in the lower expression levels of its downstream target genes such as ACC1/2, fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD) [4••,36] (Table 1, Fig. 2). The molecular mechanism by which Cideb controls the expression levels of SREBP1c remains to be an intensive area of future research.

Figure 2

Figure 2

Fsp27−/− mice also have dramatically lower levels of TAG and much smaller lipid droplets in their white adipocytes and are protected from diet-induced obesity. Fsp27−/− mice also have higher glucose uptake rates and improved insulin sensitivity [5••,6••]. Furthermore, Fsp27 deficiency leads to a reduction in fat accumulation and improved insulin sensitivity in leptin-deficient ob/ob mice. The increased insulin sensitivity in Fsp27−/− mice is likely due to increased expression and phosphorylation of crucial factors such as GLUT4, IRS-1, and AKT2 in insulin signaling pathway in the WAT. The Fsp27−/− mice also have higher lipolysis rates, especially the basal lipolysis rate. Significantly increased mitochondrial volume and activity was observed in the WAT of Fsp27−/− mice as well. Interestingly, Fsp27−/− WAT tends to acquire properties of BAT, such as smaller lipid droplets, increased mitochondrial activity, and enhanced expression of BAT-specific genes such as Ucp1, Cidea, PPARα, and Dio2. The attainment of BAT-like property in the WAT of Fsp27−/− mice is likely due to reduced expression levels of factors such as Rb, p107, and RIP140 that help to maintain WAT identity and increased levels of key metabolic regulators such as FoxC2, PPAR, and PGC-1α [37] (Table 1, Fig. 3).

Figure 3

Figure 3

Importantly, function of Cidea seems to be conserved between mouse and human. It has been reported that a V115F polymorphism in human Cidea is associated with obesity in both Swedish and Japanese populations [38,39]. Its expression levels are inversely correlated with basal metabolic rates [40]. Consistent with the observation that Cidea regulates lipolysis in BAT, Cidea was shown to control lipolysis in human adipocyte [7]. In addition, elevated Cidea was observed in the liver of diabetic mice [41]. In WAT of BMI-matched obese humans, levels of Cidea and Cidec are positively correlated with insulin sensitivity indicating their role in controlling adipose lipolysis and thus circulating fatty acids [25•]. Furthermore, levels of Cidec were reduced in response to a reduced caloric intake in obese patients [42]. Overall, these data suggest that CIDE proteins are novel regulators of the development of metabolic diseases, such as obesity, type 2 diabetes, and liver steatosis.

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Molecular mechanism for CIDE proteins in regulating metabolic disorders

Although the role of CIDE proteins in the development of metabolic disorders is well established, the molecular basis by which CIDE proteins control metabolism in adipose tissues and hepatocytes has just begun to be elucidated. It has been shown that Cidea controls the protein levels and activity of AMP-activated protein kinase (AMPK), a pivotal enzyme regulating energy homoeostasis in BAT [3]. Cidea can specifically interact with AMPK-β subunit and promote the ubiquitination-mediated proteosome degradation of AMPK complex. Consistent with this, AMPK protein levels and enzymatic activity were significantly increased in the BAT of Cidea/ mice and in differentiated mouse embryonic fibroblasts (MEFs)-derived Cidea−/− mice. Therefore, increased AMPK levels and its enzymatic activity lead to significantly increased fatty acid β-oxidation in Cidea/ adipocytes. This provides a molecular explanation for the increased energy expenditure and lean phenotype in Cidea/ mice (Fig. 1). The physiological role of Cidea in controlling AMPK stability and activity might be extended to tissues other than BAT. It has been reported that resveratrol improves high-calorie diet-induced fatty liver and extends the life span in mice at least in part through activating liver AMPK. Notably, this drug dramatically downregulates Cidea mRNA levels in liver [43]. Further experiments are needed to determine whether these two events are directly related.

Recently, it is shown that when overexpressed, Fsp27 can increase lipid droplet size and enhance the accumulation of neutral lipids [6••,12,27••,44]. These observations are consistent with the phenotype of Fsp27−/− mice, suggesting that Fsp27 plays a direct role in controlling lipid droplet size and lipid storage. The role of Fsp27 in promoting lipid droplet formation is not restricted to adipocytes. High levels of Fsp27 were detected in the liver of leptin-deficient ob/ob mice [5••]. Concomitant with the extensive changes in lipid droplet morphology and TAG content, profound changes of transcriptional network occurred in Fsp27/ adipocytes [5••]. It is important to note that change of gene expression profile is most significant in Fsp27/ WAT compared with differentiated Fsp27/ MEFs and Fsp27 knockdown 3T3-L1 cells. These observations suggest that transcriptional regulation by Fsp27 is not a cell autonomous event but requires exogenous factors such as T3 [5••].

The molecular basis by which CIDE proteins regulate downstream target gene expression remains unclear. CIDE proteins could regulate the production of specific lipid metabolites that in turn control the transcription factors and their downstream target genes. Lipid metabolites were shown to be powerful regulators of transcription via their action on crucial transcriptional factors such as PPAR, liver X receptor (LXR), and retinoic acid receptor (RAR)/RXR [45]. It is also found that C16: 1n7-palmitoleate secreted from adipose tissue can act as lipokine to regulate systemic metabolism [46]. The increased lipolysis in Fsp27/ adipocytes might provide source for bioactive fatty acids. Furthermore, many enzymes involved in lipid metabolism are localized on ER and lipid droplet through which CIDE family proteins might control the metabolites' production [28] (Fig. 3). Alternatively, it is reported that Cidea can translocate into the nucleus upon O-linked glycosylation, suggesting that CIDE may have a direct role in the nucleus [22]. It remains to be determined if the CIDE proteins may act as transcription factors.

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Conclusion

CIDE proteins play important roles in controlling diverse metabolic processes such as lipolysis, fatty acid oxidation, mitochondria activity, lipid droplet formation, and lipid storage in adipocytes and hepatocytes. Much effort will be needed to elucidate the mechanism by which CIDE proteins modulate metabolic pathways and gene expression. Furthermore, CIDE proteins may well represent new drug targets for developing therapeutical drugs for the treatment of metabolic disorders.

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Acknowledgements

We thank members in Peng Li's laboratory in Tsinghua University for helpful discussion and Dr S.C. Lin for the critical editing of the manuscript. This work was supported by grants (30530350 to P.L.) from National Natural Science Foundation of China; (704002 to P.L.) from Ministry of Education of China; National Basic Research program of China (2006CB503900, 2007CB914404) from Ministry of Science and Technology of China.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 141).

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Keywords:

Cidea; Cideb; Fsp27; lipid droplets; metabolic disorders

© 2009 Lippincott Williams & Wilkins, Inc.