Metabolic nuclear receptor signaling and the inflammatory acute phase response

Venteclef, Nicolas; Jakobsson, Tomas; Steffensen, Knut R.; Treuter, Eckardt

doi:10.1016/j.tem.2011.04.004

Cited by 91 publications

(73 citation statements)

References 81 publications

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“…4A). APR is usually invoked and synthesized by hepatocytes when the integrity of the organism is breached (26), and, if it is not activated, this likely indicates liver failure due to severe liver injury (27) instead of direct effects caused by SRSF2 deficiency. Similarly, upregulation of genes involved in the stress response or inflammatory response is possibly caused by secondary effects of SRSF2 loss.…”

Section: Resultsmentioning

confidence: 99%

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Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice

Cheng

Luo

et al. 2016

Molecular and Cellular Biology

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The liver performs a variety of unique functions critical for metabolic homeostasis. Here, we show that mice lacking the splicing factor SRSF2 but not SRSF1 in hepatocytes have severe liver pathology and biochemical abnormalities. Histological analyses revealed generalized hepatitis with the presence of ballooned hepatocytes and evidence of fibrosis. Molecular analysis demonstrated that SRSF2 governs splicing of multiple genes involved in the stress-induced cell death pathway in the liver. More importantly, SRSF2 also functions as a potent transcription activator, required for efficient expression of transcription factors mainly responsible for energy homeostasis and bile acid metabolism in the liver. Consistent with the effects of SRSF2 in gene regulation, accumulation of total cholesterol and bile acids was prominently observed in the mutant liver, followed by enhanced generation of reactive oxygen species and increased endoplasmic reticulum stress, as revealed by biochemical and ultrastructural analyses. Taking these observations together, inactivation of SRSF2 in liver caused dysregulated splicing events and hepatic metabolic disorders, which trigger endoplasmic reticulum stress, oxidative stress, and finally liver failure.A lternative splicing is a major driving force for expanding proteomic diversity that allows expression of protein variants critical for cell-or tissue-specific functions from a single gene (1). Splicing regulation is primarily achieved by the association of splicing factors with specific splicing elements on the pre-mRNA that determine whether to include or exclude an alternative exon (2, 3). Alterations in splicing factors or mutations in their target sequences result in dysregulated splicing products, which have been implicated in a wide range of human diseases (4, 5).Serine/arginine-rich (SRSF, previously named SR) proteins are a class of highly conserved RNA binding proteins with well-established roles in both constitutive and alternative splicing (AS) (2, 3, 6). They consist of one or two N-terminal RNA binding domains which allow binding to specific RNA sequences, a hinge region, and a C-terminal arginine/serine-rich domain responsible for protein-protein interaction (7). Apart from splicing-related functions, SRSF proteins have also been involved in other cellular processes, including mRNA nuclear export, mRNA stability, genomic stability, and translational control (8).Although most SRSF proteins show similar preferences for purine-rich motifs, individual SRSF proteins display distinct roles in cell physiology and vertebrate development. Specifically, deletion of SRSF1 in heart affects the splicing transition of the CaMKII␦ pre-mRNA during postnatal heart remodeling, causing severe excitation-contraction (EC) coupling defects in mice (9). Tissuespecific inactivation of SRSF2 had dramatic consequences on thymus development and caused T cell maturation defects (10). These findings strongly indicate that SRSF proteins act as tissuespecific regulators that play defined and nonredundant...

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Section: Resultsmentioning

confidence: 99%

“…6E). However, many well-known APR genes, such as Orm1, Crp, Mbl1, and Saa, which constitute systemic inflammatory components of innate immunity (26), were greatly repressed, likely reflecting liver failure following SRSF2 deletion.…”

Section: Resultsmentioning

confidence: 99%

Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice

Cheng

Luo

et al. 2016

Molecular and Cellular Biology

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“…Numerous studies emphasize the crucial involvement of transcriptional corepressor complexes linked to histone deacetylation in inflammatory gene regulation (20,26,27). Among various candidates, complexes assembled by 2 related corepressors, silencing mediator of retinoid and thyroid receptor (SMRT) and nuclear receptor corepressor 1 (NCOR1), have emerged as key players in the repression of inflammatory gene transcription, at least in macrophages (28) and in hepatocytes (29).…”

Section: Introductionmentioning

confidence: 99%

SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation

Toubal¹,

Clément²,

Fan³

et al. 2012

J. Clin. Invest.

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Low-grade chronic inflammation is a major characteristic of obesity and results from deregulated white adipose tissue function. Consequently, there is interest in identifying the underlying regulatory mechanisms and components that drive adipocyte inflammation. Here, we report that expression of the transcriptional corepressor complex subunits GPS2 and SMRT was significantly reduced in obese adipose tissue, inversely correlated to inflammatory status, and was restored upon gastric bypass surgery-induced weight loss in morbid obesity. These alterations correlated with reduced occupancy of the corepressor complex at inflammatory promoters, providing a mechanistic explanation for elevated inflammatory transcription. In support of these correlations, RNAi-mediated depletion of GPS2 and SMRT from cultured human adipocytes promoted derepression of inflammatory transcription and elevation of obesity-associated inflammatory markers, such as IL-6 and MCP-1. Furthermore, we identified a regulatory cascade containing PPARγ and TWIST1 that controlled the expression of GPS2 and SMRT in human adipocytes. These findings were clinically relevant, because treatment of diabetic obese patients with pioglitazone, an antidiabetic and antiinflammatory PPARγ agonist, restored expression of TWIST1, GPS2, and SMRT in adipose tissue. Collectively, our findings identify alterations in a regulatory transcriptional network in adipocytes involving the dysregulation of a specific corepressor complex as among the initiating events promoting adipose tissue inflammation in human obesity.

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“…However, if the regulation of these genes indeed represents cellular antiviral defence or off-target effects, they do not seem to cause a deviant liver or ovarian phenotype in the LRH-1-KD mice. Alternatively, regulation of these pathways could be a consequence of the role of LRH-1 in immunological responses (Lin et al 2000;Mueller et al 2006;Venteclef et al 2006Venteclef et al , 2011Coste et al 2007), or an immunological response to the increase cellular debris from atretic antral follicles (Hakuno et al 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Compounds modulating the activity of LRH-1 could represent an attractive new therapy for multiple indications because LRH-1 has been implicated in the inflammatory response, tumour formation, bile acid homeostasis and fertility (Botrugno et al 2004;Schoonjans et al 2005;Mueller et al 2006;Venteclef et al 2006Venteclef et al , 2011Coste et al 2007;Mataki et al 2007;Duggavathi et al 2008;Lee et al 2008;Out et al 2011). The crystal structure of LRH-1 in complex with cofactor peptides reveals the presence of phospholipids in the ligand-binding domain, indicating that the activity of LRH-1 can potentially be modulated (Ortlund et al 2005;Burendahl et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model

Gerrits

Paradé

Koonen-Reemst

et al. 2014

Reprod. Fertil. Dev.

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Abstract. Liver receptor homologue-1 (LRH-1) is an orphan nuclear receptor that has been implicated in steroid hormone biosynthesis and fertility. Herein we describe a transgenic inducible short hairpin (sh) RNA mouse model that was used to study the effect of transient LRH-1 knockdown in vivo. Induction of expression of the shRNA directed against LRH-1 for 2-6 weeks resulted in 80% knockdown of LRH-1 protein in the ovary and complete infertility. Gonadotropin hyperstimulation could not rescue the observed defects in ovulation and corpus luteum formation in LRH-1-knockdown mice. The infertility phenotype was fully reversible because LRH-1-knockdown females became pregnant and delivered normal size litters and healthy pups after cessation of LRH-1 shRNA expression. Timed ovarian microarray analysis showed that, in line with the observed decrease in plasma progesterone levels, key steroid biosynthesis genes, namely Star, Cyp11a1, Hsd3b and Scarb1, were downregulated in LRH-1-knockdown ovaries. In contrast with what has been described previously, no clear effect was observed on oestrogenic activity in LRH-1-knockdown mice. Only Sult1e1 and, surprisingly, Hsd17b7 expression was modulated with potentially opposite effects on oestradiol bioavailability. In conclusion, the fully reversible infertility phenotype of LRH-1-knockdown mice shows the feasibility of an LRH-1 antagonist as new contraceptive therapy with a mechanism of action that most prominently affects cholesterol availability and progesterone production.

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Metabolic nuclear receptor signaling and the inflammatory acute phase response

Cited by 91 publications

References 81 publications

Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice

Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice

SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation

Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model

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