HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1195349 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31639810_1.fastq.gz | Fastqsanger.gz | |||
| SRR31639810_2.fastq.gz | Fastqsanger.gz | |||
| SRR31639812_1.fastq.gz | Fastqsanger.gz | |||
| SRR31639812_2.fastq.gz | Fastqsanger.gz |
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Project description:Lipid accumulation in the renal tubules is a major determinant of diabetic kidney disease (DKD), and activation of SREBPs plays a central role in this process. Our study aimed to explore whether HSPA8, a molecular chaperone, is the master regulator of INSIG/SREBPs function in DKD. Here, we showed that tubular epithelial cell (TEC)-specific knockout of HSPA8 upregulated the phosphorylation of INSIG1 and INSIG2, which disrupted the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, and the activation of SREBPs. TEC-specific overexpression of HSPA8 restrained these changes. INSIG1 and INSIG2 can be phosphorylated by protein kinase R (PKR), while HSPA8 can recognize PKR and recruit the E3 ubiquitin ligase (CHIP) to promote PKR ubiquitination and degradation. SREBP1 transcriptionally activated HSPA8 expression under temporary hyperglycemic stimulation. However, persistent hyperglycemia reduced HSPA8 levels by promoting nuclear factor (NF)-κB-mediated transcriptional inhibition and reducing USP43-mediated deubiquitination of HSPA8. Collectively, these findings indicate that the molecular chaperone HSPA8 serves as a negative feedback regulator of SREBPs, lipogenesis, and DKD development.
2024-12-12 | GSE283754 | GEO
Project description:Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is characterized by hepatic steatosis and hepatocellular injury and progresses to cirrhosis and hepatocellular carcinoma. Sterol regulatory element-binding proteins (SREBPs) are master regulators of lipogenesis. Liver-specific PTEN knockout (KO) mice show constitutive upregulation of SREBP through PI3K-Akt pathway activation, leading to spontaneous fatty liver and subsequent HCC development. SREBP cleavage-activating protein (SCAP) plays a critical role in SREBP activation. We sought to determine the impact of SREBP inhibition on NASH and HCC development. To this end, we additionally inhibited SREBP pathway in liver-specific PTEN mice by ablating SCAP and generated liver-specific PTEN/SCAP double KO (DKO) mice. However unexpectedly, inhibition of SCAP/SREBP pathway markedly exacerbated liver injury (5weeks), fibrosis (5months), and carcinogenesis (7 months) in PTEN KO mice. To elucidate the mechanisms of liver injury in liver-specific PTEN/SCAP DKO mice, we conducted transcriptome analyses of the livers.
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Project description:In this study, we studied the genomic responses of the Insig and Scap deletion from perinatal lung. Through comprehensive data analysis and integration, time dependent effects of epithelial SCAP/INSIG/SREBP deletion and defined SCAP/INSIG/SREBP-associated genes, bioprocesses and downstream pathways were identified. Total lung RNA was isolated from Scapdelata/delta, Insig1/2delta/delta, and respective control littermates at E17.5, E18.5 and PN1 were used for mRNA expression profiling analysis (n=3 for each condition)
2014-07-10 | E-GEOD-53397 | biostudies-arrayexpress
Project description:Pulmonary function after birth is dependent upon surfactant lipids that reduce surface tension in the alveoli. The sterol-responsive element-binding proteins (SREBPs) are transcription factors regulating expression of genes controlling lipid homeostasis in many tissues. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap∆/∆) in vivo. Prior to birth (E18.5), deletion of Scap decreased the expression of both SREBPs and a number of genes regulating fatty acid and cholesterol metabolism. Nevertheless, Scap∆/∆ mice survived postnatally, surfactant and lung tissue lipids being substantially normalized in adult Scap∆/∆ mice. Although phospholipid synthesis was decreased in type II cells from adult Scap∆/∆ mice, lipid storage, synthesis, and transfer by lung lipofibroblasts were increased. mRNA microarray data indicated that SCAP influenced two major gene networks, one regulating lipid metabolism and the other stress-related responses. Deletion of the SCAP/SREBP pathway in respiratory epithelial cells altered lung lipid homeostasis and induced compensatory lipid accumulation and synthesis in lung lipofibroblasts. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap∆/∆) in vivo.Lung cRNA was hybridized to the murine genome MOE430 V2 chips.
2011-01-08 | E-GEOD-26496 | biostudies-arrayexpress
Project description:In this study, we studied the genomic responses of the Insig and Scap deletion from perinatal lung. Through comprehensive data analysis and integration, time dependent effects of epithelial SCAP/INSIG/SREBP deletion and defined SCAP/INSIG/SREBP-associated genes, bioprocesses and downstream pathways were identified.
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Project description:Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is characterized by hepatic steatosis and hepatocellular injury and progresss cirrhosis and hepatocellular carcinoma. Sterol regulatory elment-binding proteins (SREBPs) are master regulators of lipogenesis. Liver-specific PTEN knockout (KO) mice show constitutive upregulation of SREBP through PI3K-Akt pathway activation, leading to spontaneous fatty liver and subsequent HCC development. SREBP cleavage-activating protein (SCAP) plays a critical role in SREBP activation. We sought to determine the impact of SREBP inhibition on NASH and HCC development. To this end, we additionaly inhibited SREBP pathway in liver-specific PTEN mice by ablating SCAP and generated liver-specific PTEN/SCAP double KO (DKO) mice. However unexpectedly, inhibition of SCAP/SREBP pathway markedly exacerbated liver injury (5weeks), fibrosis (5months), and carcinogenesis (7 months) in PTEN KO mice. To elucidate the mechanisms of liver tumorigenesis in liver-specific PTEN/SCAP DKO mice, we conducted transcriptome analyses of the livers.
2022-04-05 | GSE174173 | GEO
Project description:Tumor growth outstrips local nutrient supply, making metabolic reprogramming a necessary component of oncogenesis and cancer progression. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell division. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for cholesterol and fatty acid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including glioblastoma, breast, colon, liver and prostate. However, the role the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrate that SREBP target genes are upregulated in PDAC tumors, and SREBPs are upregulated in patient-derived PDAC cell lines under low serum conditions that mimic the tumor microenvironment. Chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Using subcutaneous and orthotopic xenograft models, we showed that SCAP is required for PDAC tumor growth. Pancreas-specific knockout of Scap had no effect on mouse pancreas development or function, allowing examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap significantly prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor inception. Collectively, these results demonstrate that SCAP and SREBP pathway activity are essential for PDAC cell and tumor growth in vitro and in vivo, identifying SCAP as a potential therapeutic target for PDAC.
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Project description:Pulmonary function after birth is dependent upon surfactant lipids that reduce surface tension in the alveoli. The sterol-responsive element-binding proteins (SREBPs) are transcription factors regulating expression of genes controlling lipid homeostasis in many tissues. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap∆/∆) in vivo. Prior to birth (E18.5), deletion of Scap decreased the expression of both SREBPs and a number of genes regulating fatty acid and cholesterol metabolism. Nevertheless, Scap∆/∆ mice survived postnatally, surfactant and lung tissue lipids being substantially normalized in adult Scap∆/∆ mice. Although phospholipid synthesis was decreased in type II cells from adult Scap∆/∆ mice, lipid storage, synthesis, and transfer by lung lipofibroblasts were increased. mRNA microarray data indicated that SCAP influenced two major gene networks, one regulating lipid metabolism and the other stress-related responses. Deletion of the SCAP/SREBP pathway in respiratory epithelial cells altered lung lipid homeostasis and induced compensatory lipid accumulation and synthesis in lung lipofibroblasts.
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