Protein Inhibitor of Activated STAT 1 (PIAS1) Is Identified as the SUMO E3 Ligase of CCAAT/Enhancer-Binding Protein β (C/EBPβ) during Adipogenesis

Liu, Yang; Zhang, Ya Dong; Guo, Liang; Huang, Hai; Zhu, Hao; Huang, Jia; Liu, Yuan; Zhou, Shui Rong; Dang, Yongjun; Li, Xi; Tang, Qi

doi:10.1128/mcb.00723-13

Cited by 47 publications

(50 citation statements)

References 50 publications

(66 reference statements)

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“…However, little is known about food factors which promote the degradation of C/EBP␤ protein. C/ EBP␤ protein is degraded by the proteasome pathway through increasing its ubiquitination (41). Our results showed that CCM promoted ubiquitination of C/EBP␤ (Fig.…”

Section: Discussionmentioning

confidence: 62%

Caffeine-Stimulated Intestinal Epithelial Cells Suppress Lipid Accumulation in Adipocytes

Mitani

Nagano

Harada

et al. 2017

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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Summary Caffeine is a methylxanthine derived from plant foods such as coffee beans and tea leaves, and has multiple biological activities against physiological response and several diseases. Although there are some reports about the direct effect of caffeine against anti-lipid accumulation in vitro, the effect of caffeine on lipid accumulation in adipocytes through stimulating intestinal epithelial cells is unknown. Since direct treatment with caffeine to 3T3-L1 cells did not affect lipid accumulation, we determined whether caffeinestimulated intestinal epithelial Caco-2 cells influence the lipid accumulation in 3T3-L1 adipocytes. Caco-2 cells were cultured on a transwell insert with or without caffeine for 24 h. Subsequently, the basolateral component of the Caco-2 cell culture on the transwell was collected and termed caffeine-conditioning medium (CCM). When 3T3-L1 adipocytes were incubated with CCM, CCM decreased lipid accumulation and suppressed gene expression of proliferator activated receptor (PPAR) ␥ and CCAAT/enhancer binding protein (C/EBP) ␣ in 3T3-L1 adipocytes. Furthermore, CCM decreased the expression of C/EBP␤ and C/EBP␦ at the protein level, but not at the mRNA level. We observed that a proteasome inhibitor, MG132, inhibited CCM-caused down-expression of C/EBP␤ and C/EBP␦ proteins, and that CCM promoted the ubiquitination level of C/EBP␤ and C/EBP␦ proteins. Protein microarray analysis showed caffeine suppresses the secretion of inflammatory cytokines, interleukin-8 and plasminogen activator inhibitor-1 from Caco-2 cells. These results suggest that caffeine indirectly suppresses lipid accumulation in 3T3-L1 adipocytes through decreasing secretion of inflammatory cytokines from Caco-2 cells. Key Words caffeine, adipogenesis, 3T3-L1 adipocytes, Caco-2 cells Obesity is a risk factor for multiple lifestyle diseases such as apoplexy, heart disease and diabetes (1, 2). Adipocytes play a critical role in regulating lipid metabolism and energy balance, which are associated with adiposity (3). An increase in the number of differentiated mature adipocytes and excess accumulation of body fat leads to adiposity. Adipocytes accumulate intracellular lipids during differentiation. As an in vitro model system for adipogenesis, murine 3T3-L1 cells, which were originally derived from mouse embryos, are often used. Differentiation of 3T3-L1 cells is induced by exposure to the inducers, such as 3-isobutyl-1-methylxanthine (IBMX), dexamethasone and insulin, and is responsible for the accumulation of a large amount of intracellular lipid droplets during adipocyte differentiation. Adipogenesis, the differentiation process for producing adipocytes, is a complex process that is regulated by various transcription factors and their related genes. The expression levels of CCAAT/enhancer binding protein (C/EBP) ␤ and C/EBP␦, as transcriptional factors, are increased in the early phase of adipocyte differentiation (4). Subsequently, these transcription factors up-regulate proliferator activated receptor (PPAR) ␥ and C/EBP␣, a...

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Section: Discussionmentioning

confidence: 62%

Caffeine-Stimulated Intestinal Epithelial Cells Suppress Lipid Accumulation in Adipocytes

Mitani

Nagano

Harada

et al. 2017

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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“…At 2 days postconfluence (designated day 0), 3T3-L1 were subjected to adipogenic differentiation as previously described (22). Adipocytes phenotype appeared on day 3 and reached maximum by day 8 postadipogenic induction.…”

Section: Reagent and Adipocyte Differentiationmentioning

confidence: 99%

“…Our previous report clarified that PIAS1 restricted adipocytes differentiation by inhibiting CCAAT-enhancerbinding protein-b (22); however, the function of PIAS1 in mature adipocytes is not clear yet. In the current study, we found that PIAS1 was downregulated in the inguinal white adipose tissue (iWAT) of prediabetic models, including leptin-deficient (ob/ob), leptin receptor-deficient (db/db), and high-fat diet (HFD) mice.…”

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confidence: 99%

“…PIAS1 was initially named for its ability to interact with and inhibit signal transducer and activator of transcription (STAT) 1 (18), but subsequent investigations have clarified that PIAS1 regulates a variety of transcription factors through distinct mechanisms, including promoting SUMOylation of target proteins and blocking the DNA-binding activity of transcription factors (19). PIAS1 plays a critical role in such cellular processes as cell proliferation (20), cell differentiation (21, 22), and immune responses (23)(24)(25). In the innate immune system, PIAS1 occupies the binding sites of STAT 1 and NF-kB on the promoters of their target genes to block expression of proinflammatory factors such as TNF-a and macrophage inflammatory protein 2 (MIP2).…”

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confidence: 99%

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Protein Inhibitor of Activated STAT 1 (PIAS1) Protects Against Obesity-Induced Insulin Resistance by Inhibiting Inflammation Cascade in Adipose Tissue

Liu

Dou

et al. 2015

Diabetes

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Obesity is associated with chronic low-level inflammation, especially in fat tissues, which contributes to insulin resistance and type 2 diabetes mellitus (T2DM). Protein inhibitor of activated STAT 1 (PIAS1) modulates a variety of cellular processes such as cell proliferation and DNA damage responses. Particularly, PIAS1 functions in the innate immune system and is a key regulator of the inflammation cascade. However, whether PIAS1 is involved in the regulation of insulin sensitivity remains unknown. Here, we demonstrated that PIAS1 expression in white adipose tissue (WAT) was downregulated by c-Jun N-terminal kinase in prediabetic mice models. Overexpression of PIAS1 in inguinal WAT of prediabetic mice significantly improved systemic insulin sensitivity, whereas knockdown of PIAS1 in wild-type mice led to insulin resistance. Mechanistically, PIAS1 inhibited the activation of stress-induced kinases and the expression of nuclear factor-κB target genes in adipocytes, mainly including proinflammatory and chemotactic factors. In doing so, PIAS1 inhibited macrophage infiltration in adipose tissue, thus suppressing amplification of the inflammation cascade, which in turn improved insulin sensitivity. These results were further verified in a fat transplantation model. Our findings shed light on the critical role of PIAS1 in controlling insulin sensitivity and suggest a therapeutic potential of PIAS1 in T2DM.

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“…Dutchak et al (22) reported that FGF21 knockout mice have a marked increase in the SUMOylation of PPAR␥ and decreased body fat, indicating that SUMOylation of PPAR␥ modulates adipogenesis. Liu et al (23) found that PIAS1 promotes C/EBP␤ SUMOylation and inhibits adipogenesis. Chung et al (24) found that a de-SUMOylation protease, SENP2, can directly modulate C/EBP␤ SUMOylation and its stability and, consequently, is essential for adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

Small Ubiquitin-like Modifier (SUMO) Protein-specific Protease 1 De-SUMOylates Sharp-1 Protein and Controls Adipocyte Differentiation

Liu

Wang

Mei³

et al. 2014

Journal of Biological Chemistry

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Protein Inhibitor of Activated STAT 1 (PIAS1) Is Identified as the SUMO E3 Ligase of CCAAT/Enhancer-Binding Protein β (C/EBPβ) during Adipogenesis

Cited by 47 publications

References 50 publications

Caffeine-Stimulated Intestinal Epithelial Cells Suppress Lipid Accumulation in Adipocytes

Caffeine-Stimulated Intestinal Epithelial Cells Suppress Lipid Accumulation in Adipocytes

Protein Inhibitor of Activated STAT 1 (PIAS1) Protects Against Obesity-Induced Insulin Resistance by Inhibiting Inflammation Cascade in Adipose Tissue

Small Ubiquitin-like Modifier (SUMO) Protein-specific Protease 1 De-SUMOylates Sharp-1 Protein and Controls Adipocyte Differentiation

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