A New Role for Sterol Regulatory Element Binding Protein 1 Transcription Factors in the Regulation of Muscle Mass and Muscle Cell Differentiation

ABSTRACT The role of the transcription factors sterol regulatory element binding protein 1a (SREBP-1a) and SREBP-1c in the regulation of cholesterol and fatty acid metabolism has been well studied; however, little is known about their specific function in muscle. In the present study, analysis of recent microarray data from muscle cells overexpressing SREBP1 suggested that they may play a role in the regulation of myogenesis. We then demonstrated that SREBP-1a and -1c inhibit myoblast-to-myotube differentiation and also induce in vivo and in vitro muscle atrophy. Furthermore, we have identified the transcriptional repressors BHLHB2 and BHLHB3 as mediators of these effects of SREBP-1a and -1c in muscle. Both repressors are SREBP-1 target genes, and they affect the expression of numerous genes involved in the myogenic program. Our findings identify a new role for SREBP-1 transcription factors in muscle, thus linking the control of muscle mass to metabolic pathways.

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cAMP-Responsive Element Binding Protein: A Vital Link in Embryonic Hormonal Adaptation

Endocrinology ◽

10.1210/en.2012-2096 ◽

2013 ◽

Vol 154 (6) ◽

pp. 2208-2221 ◽

Cited By ~ 13

Author(s):

Maria Schindler ◽

Sünje Fischer ◽

René Thieme ◽

Bernd Fischer ◽

Anne Navarrete Santos

Keyword(s):

Transcription Factors ◽

Target Genes ◽

Binding Protein ◽

Cell Lineage ◽

Element Binding Protein ◽

A Cell ◽

Responsive Element ◽

Camp Responsive Element Binding

Abstract The transcription factor cAMP responsive element-binding protein (CREB) and activating transcription factors (ATFs) are downstream components of the insulin/IGF cascade, playing crucial roles in maintaining cell viability and embryo survival. One of the CREB target genes is adiponectin, which acts synergistically with insulin. We have studied the CREB-ATF-adiponectin network in rabbit preimplantation development in vivo and in vitro. From the blastocyst stage onwards, CREB and ATF1, ATF3, and ATF4 are present with increasing expression for CREB, ATF1, and ATF3 during gastrulation and with a dominant expression in the embryoblast (EB). In vitro stimulation with insulin and IGF-I reduced CREB and ATF1 transcripts by approximately 50%, whereas CREB phosphorylation was increased. Activation of CREB was accompanied by subsequent reduction in adiponectin and adiponectin receptor (adipoR)1 expression. Under in vivo conditions of diabetes type 1, maternal adiponectin levels were up-regulated in serum and endometrium. Embryonic CREB expression was altered in a cell lineage-specific pattern. Although in EB cells CREB localization did not change, it was translocated from the nucleus into the cytosol in trophoblast (TB) cells. In TB, adiponectin expression was increased (diabetic 427.8 ± 59.3 pg/mL vs normoinsulinaemic 143.9 ± 26.5 pg/mL), whereas it was no longer measureable in the EB. Analysis of embryonic adipoRs showed an increased expression of adipoR1 and no changes in adipoR2 transcription. We conclude that the transcription factors CREB and ATFs vitally participate in embryo-maternal cross talk before implantation in a cell lineage-specific manner. Embryonic CREB/ATFs act as insulin/IGF sensors. Lack of insulin is compensated by a CREB-mediated adiponectin expression, which may maintain glucose uptake in blastocysts grown in diabetic mothers.

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Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1714518115 ◽

2018 ◽

Vol 115 (20) ◽

pp. E4680-E4689 ◽

Cited By ~ 29

Author(s):

Evan D. Muse ◽

Shan Yu ◽

Chantle R. Edillor ◽

Jenhan Tao ◽

Nathanael J. Spann ◽

...

Keyword(s):

Target Genes ◽

Fatty Acid Biosynthesis ◽

Regulatory Element ◽

Element Binding Protein ◽

Cholesterol Biosynthetic Pathway ◽

Sterol Regulatory Element ◽

X Receptors ◽

Lxr Agonists

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia.

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Docosahexaenoic Acid Suppresses Expression of Adipogenic Tetranectin through Sterol Regulatory Element-Binding Protein and Forkhead Box O Protein in Pigs

Nutrients ◽

10.3390/nu13072315 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2315

Author(s):

Jui-Ting Yang ◽

Yu-Jen Chen ◽

Chao-Wei Huang ◽

Ya-Chin Wang ◽

Harry J. Mersmann ◽

...

Keyword(s):

Fatty Acids ◽

Binding Sites ◽

Binding Protein ◽

Regulatory Element ◽

Forkhead Box ◽

Transcriptional Suppression ◽

Element Binding Protein ◽

Sterol Regulatory Element

Tetranectin (TN), a plasminogen-binding protein originally involved in fibrinolysis and bone formation, was later identified as a secreted adipokine from human and rat adipocytes and positively correlated with adipogenesis and lipid metabolism in adipocytes. To elucidate the nutritional regulation of adipogenic TN from diets containing different sources of fatty acids (saturated, n-6, n-3) in adipocytes, we cloned the coding region of porcine TN from a cDNA library and analyzed tissue expressions in weaned piglets fed with 2% soybean oil (SB, enriched in n-6 fatty acids), docosahexaenoic acid oil (DHA, an n-3 fatty acid) or beef tallow (BT, enriched in saturated and n-9 fatty acids) for 30 d. Compared with tissues in the BT- or SB-fed group, expression of TN was reduced in the adipose, liver and lung tissues from the DHA-fed group, accompanied with lowered plasma levels of triglycerides and cholesterols. This in vivo reduction was also confirmed in porcine primary differentiated adipocytes supplemented with DHA in vitro. Then, promoter analysis was performed. A 1956-bp putative porcine TN promoter was cloned and transcription binding sites for sterol regulatory-element binding protein (SREBP)-1c or forkhead box O proteins (FoxO) were predicted on the TN promoter. Mutating binding sites on porcine TN promoters showed that transcriptional suppression of TN by DHA on promoter activity was dependent on specific response elements for SREBP-1c or FoxO. The inhibited luciferase promoter activity by DHA on the TN promoter coincides with reduced gene expression of TN, SREBP-1c, and FoxO1 in human embryonic kidney HEK293T cells supplemented with DHA. To conclude, our current study demonstrated that the adipogenic TN was negatively regulated by nutritional modulation of DHA both in pigs in vivo and in humans/pigs in vitro. The transcriptional suppression by DHA on TN expression was partly through SREBP-1c or FoxO. Therefore, down-regulation of adipogenic tetranectin associated with fibrinolysis and adipogenesis may contribute to the beneficial effects of DHA on ameliorating obesity-induced metabolic syndromes such as atherosclerosis and adipose dysfunctions.

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Analysis of Sterol-Regulatory Element-Binding Protein 1c Target Genes in Mouse Liver during Aging and High-Fat Diet

Journal of Nutrigenetics and Nutrigenomics ◽

10.1159/000350751 ◽

2013 ◽

Vol 6 (2) ◽

pp. 107-122 ◽

Cited By ~ 10

Author(s):

Frédéric Capel ◽

Gaëlle Rolland-Valognes ◽

Catherine Dacquet ◽

Manuel Brun ◽

Michel Lonchampt ◽

...

Keyword(s):

High Fat Diet ◽

Mouse Liver ◽

Target Genes ◽

Binding Protein ◽

Regulatory Element ◽

High Fat ◽

Element Binding Protein ◽

Sterol Regulatory Element

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Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00059.2004 ◽

2004 ◽

Vol 287 (6) ◽

pp. E1039-E1048 ◽

Cited By ~ 32

Author(s):

Caroline Améen ◽

Daniel Lindén ◽

Britt-Mari Larsson ◽

Agneta Mode ◽

Agneta Holmäng ◽

...

Keyword(s):

Insulin Sensitivity ◽

Continuous Infusion ◽

Target Genes ◽

Binding Protein ◽

Regulatory Element ◽

Female Rats ◽

Mrna Levels ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Secretory Pattern

We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female- and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-α (LXRα) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXRα mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXRα mRNA but is associated with decreased insulin sensitivity.

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Selective Association of Sterol Regulatory Element-binding Protein Isoforms with Target Promoters in Vivo

Journal of Biological Chemistry ◽

10.1074/jbc.m404693200 ◽

2004 ◽

Vol 279 (36) ◽

pp. 37360-37367 ◽

Cited By ~ 26

Author(s):

Mary K. Bennett ◽

Julia I. Toth ◽

Timothy F. Osborne

Keyword(s):

Binding Protein ◽

Regulatory Element ◽

Protein Isoforms ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Target Promoters

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Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression

Cellular Physiology and Biochemistry ◽

10.1159/000369739 ◽

2015 ◽

Vol 35 (2) ◽

pp. 803-815 ◽

Cited By ~ 12

Author(s):

Andreas Bitter ◽

Andreas K. Nüssler ◽

Wolfgang E. Thasler ◽

Kathrin Klein ◽

Ulrich M. Zanger ◽

...

Keyword(s):

Gene Expression ◽

Human Liver ◽

Target Genes ◽

Binding Protein ◽

Regulatory Element ◽

Lipogenic Gene ◽

Knock Down ◽

Lipogenic Gene Expression ◽

Element Binding Protein ◽

Sterol Regulatory Element

Background/Aims: Sterol regulatory element-binding protein (SREBP) 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. Methods: mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. Results: In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. Conclusion: We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.

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