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Fam57b (family with sequence similarity 57, member B), a novel peroxisome proliferator-activated receptor ? target gene that regulates adipogenesis through ceramide synthesis.

ABSTRACT: This report identifies a novel gene encoding Fam57b (family with sequence similarity 57, member B) as a novel peroxisome proliferator-activated receptor ? (PPAR?)-responsive transmembrane gene that is related to obesity. The gene was identified based on an integrated bioinformatics analysis of the following three expression profiling data sets: adipocyte differentiation of mouse stromal cells (ST2 cells), adipose tissues from obesity mice, and siRNA-mediated knockdown of Ppar? using ST2 cells. Fam57b consists of three variants expressed from different promoters and contains a Tram-Lag1-CLN8 domain that is related to ceramide synthase. Reporter and ChIP assays showed that Fam57b variant 2 is a bona fide PPAR? target gene in ST2 cells. Fam57b was up-regulated during adipocyte differentiation, suggesting that FAM57B is involved in this process. Surprisingly, FAM57B overexpression inhibited adipogenesis, and siRNA-mediated knockdown promoted adipocyte differentiation. Analysis of the ceramide content by lipid assay found that ceramides were in fact augmented in FAM57B-overexpressing ST2 cells. We also confirmed that ceramide inhibits adipogenesis. Therefore, the aforementioned results of FAM57B overexpression and siRNA experiments are reconciled by ceramide synthesis. In summary, we present in vitro evidence showing that PPAR? regulates Fam57b transcription during the adipogenesis of ST2 cells. In addition, our results suggest that PPAR? activation contributes to the regulation of ceramide metabolism during adipogenesis via FAM57B.

SUBMITTER: Yamashita-Sugahara Y

PROVIDER: S-EPMC3576059 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Fam57b (family with sequence similarity 57, member B), a novel peroxisome proliferator-activated receptor γ target gene that regulates adipogenesis through ceramide synthesis.

Yamashita-Sugahara Yzumi Y Tokuzawa Yoshimi Y Nakachi Yutaka Y Kanesaki-Yatsuka Yukiko Y Matsumoto Masahito M Mizuno Yosuke Y Okazaki Yasushi Y

The Journal of biological chemistry 20121228 7

This report identifies a novel gene encoding Fam57b (family with sequence similarity 57, member B) as a novel peroxisome proliferator-activated receptor γ (PPARγ)-responsive transmembrane gene that is related to obesity. The gene was identified based on an integrated bioinformatics analysis of the following three expression profiling data sets: adipocyte differentiation of mouse stromal cells (ST2 cells), adipose tissues from obesity mice, and siRNA-mediated knockdown of Pparγ using ST2 cells. F ...[more]

PMID: 23275342

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Project description:ABCA12 (ATP binding cassette transporter, family 12) is a cellular membrane transporter that facilitates the delivery of glucosylceramides to epidermal lamellar bodies in keratinocytes, a process that is critical for permeability barrier formation. Following secretion of lamellar bodies into the stratum corneum, glucosylceramides are metabolized to ceramides, which comprise approximately 50% of the lipid in stratum corneum. Gene mutations of ABCA12 underlie harlequin ichthyosis, a devastating skin disorder characterized by abnormal lamellar bodies and a severe barrier abnormality. Recently we reported that peroxisome proliferator-activated receptor (PPAR) and liver X receptor activators increase ABCA12 expression in human keratinocytes. Here we demonstrate that ceramide (C(2)-Cer and C(6)-Cer), but not C(8)-glucosylceramides, sphingosine, or ceramide 1-phosphate, increases ABCA12 mRNA expression in a dose- and time-dependent manner. Inhibitors of glucosylceramide synthase, sphingomyelin synthase, and ceramidase and small interfering RNA knockdown of human alkaline ceramidase, which all increase endogenous ceramide levels, also increased ABCA12 mRNA levels. Moreover, simultaneous treatment with C(6)-Cer and each of these same inhibitors additively increased ABCA12 expression, indicating that ceramide is an important inducer of ABCA12 expression and that the conversion of ceramide to other sphingolipids or metabolites is not required. Finally, both exogenous and endogenous ceramides preferentially stimulate PPARdelta expression (but not other PPARs or liver X receptors), whereas PPARdelta knockdown by siRNA transfection specifically diminished the ceramide-induced increase in ABCA12 mRNA levels, indicating that PPARdelta is a mediator of the ceramide effect. Together, these results show that ceramide, an important lipid component of epidermis, up-regulates ABCA12 expression via the PPARdelta-mediated signaling pathway, providing a substrate-driven, feed-forward mechanism for regulating this key lipid transporter.

Dataset Information

Fam57b (family with sequence similarity 57, member B), a novel peroxisome proliferator-activated receptor ? target gene that regulates adipogenesis through ceramide synthesis.

Publications

Fam57b (family with sequence similarity 57, member B), a novel peroxisome proliferator-activated receptor γ target gene that regulates adipogenesis through ceramide synthesis.

Similar Datasets

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