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The cAMP-responsive element binding protein (CREB) regulates the expression of acid ceramidase (ASAH1) in H295R human adrenocortical cells.

ABSTRACT: Acid ceramidase (encoded by ASAH1) is a lipid hydrolase that catalyzes the conversion of ceramide (cer) into sphingosine (SPH) and a free fatty acid. Adrenocortical steroidogenesis is regulated by the trophic peptide hormone adrenocorticotropin (ACTH), which induces the expression of steroidogenic genes in the human adrenal cortex primarily via a cAMP/protein kinase A (PKA)-dependent pathway. ACTH also stimulates sphingolipid metabolism in H295R adrenocortical cells leading to changes in steroidogenic gene expression. Based on our previous data identifying SPH as an antagonist for the nuclear receptor steroidogenic factor 1 (SF-1) and the role of ACTH-stimulated changes in sphingolipid metabolism on steroidogenic gene transcription, the aim of the current study was to determine the role of ACTH signaling in regulating the expression of the ASAH1 gene in H295R cells. We show that activation of the ACTH signaling pathway induces ASAH1 gene expression by stimulating the binding of the cAMP-responsive element binding protein (CREB) to multiple regions of the ASAH1 promoter. CREB binding promotes the recruitment of the coactivators CREB binding protein (CBP) and p300 to the CREB-responsive regions of the promoter. Consistent with transcriptional activation, we show that cAMP signaling increases the trimethylation of Lys 4 on histone H3 (H3K4) along the ASAH1 promoter. Finally, RNA interference (RNAi) experiments demonstrate that CREB is indispensable for cAMP-induced ASAH1 transcription. These data identify the ACTH/cAMP signaling pathway and CREB as transcriptional regulators of the ASAH1 gene in the human adrenal cortex.

SUBMITTER: Lucki N

PROVIDER: S-EPMC3976422 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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The cAMP-responsive element binding protein (CREB) regulates the expression of acid ceramidase (ASAH1) in H295R human adrenocortical cells.

Lucki Natasha N Sewer Marion B MB

Biochimica et biophysica acta 20090316 8

Acid ceramidase (encoded by ASAH1) is a lipid hydrolase that catalyzes the conversion of ceramide (cer) into sphingosine (SPH) and a free fatty acid. Adrenocortical steroidogenesis is regulated by the trophic peptide hormone adrenocorticotropin (ACTH), which induces the expression of steroidogenic genes in the human adrenal cortex primarily via a cAMP/protein kinase A (PKA)-dependent pathway. ACTH also stimulates sphingolipid metabolism in H295R adrenocortical cells leading to changes in steroid ...[more]

PMID: 19298866

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Project description:Background and aimsHigh plasma lipid/lipoprotein levels are risk factors for various metabolic diseases. We previously showed that circadian rhythms regulate plasma lipids and deregulation of these rhythms causes hyperlipidemia and atherosclerosis in mice. Here, we show that global and liver-specific brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1)-deficient mice maintained on a chow or Western diet developed hyperlipidemia, denoted by the presence of higher amounts of triglyceride-rich and apolipoprotein AIV (ApoAIV)-rich larger chylomicron and VLDL due to overproduction.Approach and resultsBmal1 deficiency decreased small heterodimer partner (Shp) and increased microsomal triglyceride transfer protein (MTP), a key protein that facilitates primordial lipoprotein assembly and secretion. Moreover, we show that Bmal1 regulates cAMP-responsive element-binding protein H (Crebh) to modulate ApoAIV expression and the assembly of larger lipoproteins. This is supported by the observation that Crebh-deficient and ApoAIV-deficient mice, along with Bmal1-deficient mice with knockdown of Crebh, had smaller lipoproteins. Further, overexpression of Bmal1 in Crebh-deficient mice had no effect on ApoAIV expression and lipoprotein size.ConclusionsThese studies indicate that regulation of ApoAIV and assembly of larger lipoproteins by Bmal1 requires Crebh. Mechanistic studies showed that Bmal1 regulates Crebh expression by two mechanisms. First, Bmal1 interacts with the Crebh promoter to control circadian regulation. Second, Bmal1 increases Rev-erbα expression, and nuclear receptor subfamily 1 group D member 1 (Nr1D1, Rev-erbα) interacts with the Crebh promoter to repress expression. In short, Bmal1 modulates both the synthesis of primordial lipoproteins and their subsequent expansion into larger lipoproteins by regulating two different proteins, MTP and ApoAIV, through two different transcription factors, Shp and Crebh. It is likely that disruptions in circadian mechanisms contribute to hyperlipidemia and that avoiding disruptions in circadian rhythms may limit/prevent hyperlipidemia and atherosclerosis.

Dataset Information

The cAMP-responsive element binding protein (CREB) regulates the expression of acid ceramidase (ASAH1) in H295R human adrenocortical cells.

Publications

The cAMP-responsive element binding protein (CREB) regulates the expression of acid ceramidase (ASAH1) in H295R human adrenocortical cells.

Similar Datasets

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