SMARCAL1 modulates cellular triglyceride storage and expenditure in response to cell growth states via interaction with ANGPTL3 (RNA-Seq 2)
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ABSTRACT:
PROVIDER: PRJNA914048 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22822758_1.fastq.gz | Fastqsanger.gz | |||
| SRR22822758_2.fastq.gz | Fastqsanger.gz | |||
| SRR22822759_1.fastq.gz | Fastqsanger.gz | |||
| SRR22822759_2.fastq.gz | Fastqsanger.gz | |||
| SRR22822760_1.fastq.gz | Fastqsanger.gz |
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Project description:SMARCAL1 is a chromatin regulator. Biallelic mutations of SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), a disease with severe growth defects and premature death. Atherosclerosis and hyperlipidemia are common phenotypes among SIOD patients. However, little is known about their genesis and development. Here we show that SMARCAL1 is vital in regulating cellular lipid metabolism. Using a proteomic approach, we found that SmarcAL1 interacts with angiopoietin-like 3 (Angptl3), a key lipoprotein regulator. SmarcAL1 deficiency in cell models resulted in substantial accumulation of triglycerides (TGs) and fatty acids (FAs). SmarcAL1 KO in mice drastically increased plasma TG level. The nuclear SmarcAL1 translocates into cytoplasm, surprisingly, enriched at peroxisomes, where it interacts with Angptl3. This shuttling provides a regulatory control over cellular lipid metabolism via SmarcAL1-regulated gene expression, in response to cell growth states. Inactivation of SmarcAL1 gene reduced the expression of the genes responsible for FA metabolism, suggesting that SmarcAL1 plays a key role in regulating lipid metabolism. Indeed, the Angptl3-mediated TG partition is largely dependent on SmarcAL1 activity. This activity was further supported by two opposite SMARCAL1 single-tissue expression profiles linked to two quantitative trait loci that are differentially associated with body mass index. Thus, SMARCAL1 is crucial for cellular lipid metabolism, and ANGPTL3-regulated SMARCAL1 activities enable cells to response to cell growth states for TG storage or expenditure.
2024-01-02 | GSE221373 | GEO
Project description:Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
2025-02-19 | GSE221371 | GEO
Project description:Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
2025-02-19 | GSE221049 | GEO
Project description:Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
2025-02-19 | GSE221048 | GEO
Project description:Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
2025-02-19 | GSE221047 | GEO
Project description:Biallelic mutations of the chromatin regulator SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), characterized by severe growth defects and premature mortality. Atherosclerosis and hyperlipidemia are common among SIOD patients, yet their onset and progression are poorly understood. Using an integrative approach involving proteomics, mouse models, and population genetics, we investigated SMARCAL1's role. We found that SmarcAL1 interacts with angiopoietin-like 3 (Angptl3), a key regulator of lipoprotein metabolism. In vitro and in vivo analyses demonstrate SmarcAL1's vital role in maintaining cellular lipid homeostasis. The observed translocation of SmarcAL1 to cytoplasmic peroxisomes suggests a potential regulatory role in lipid metabolism through gene expression. SmarcAL1 gene inactivation reduces the expression of key genes in cellular lipid catabolism. Population genetics investigations highlight significant associations between SMARCAL1 genetic variations and body mass index, along with lipid-related traits. This study underscores SMARCAL1's pivotal role in cellular lipid metabolism, likely contributing to the observed lipid phenotypes in SIOD patients.
2025-02-19 | GSE221372 | GEO
Project description:Cardiovascular disease is a leading cause of death worldwide, and inhibition of the hepatically secreted protein ANGPTL3 has emerged as an effective treatment for lowering low-density lipoprotein cholesterol (LDL), the cardinal risk factor for coronary artery disease (CAD). In this study, we examine the effects of complete genetic deficiency of ANGPTL3 on the hepatocyte transcriptome using a HepG2 cell culture model with the ANGPTL3 locus "knocked out" (KO) via CRISPR-Cas9.
2023-05-15 | GSE232045 | GEO
Project description:Members of the Estrogen-Related Receptor (ERR) family of nuclear receptors (NR) serve a key role in coordinating triglyceride (TAG) accumulation with juvenile growth and development. In both insects and mammals, loss of ERR activity disrupts (TAG) storage during the post-embryonic growth phase, with loss-of-function mutations in mouseErraandDrosophila melanogaster dERRinducing a lean phenotype. However, the role of insect ERRs in controlling TAG accumulation remains poorly understood, as previous multiomic studies largely relied on whole animal analyses. Here we address this shortcoming by using tissue-specific approaches to determine how dERR regulates lipid metabolism within theDrosophilalarval fat body. We found that dERR autonomously promotes TAG accumulation within fat body cells by regulating expression of genes involved in glycolysis, the pentose phosphate pathway, lipid synthesis, andb-oxidation. As an extension of these results, we not only discovered thatdERRmutant fat bodies exhibit decreased expression of known HNF4 target genes but also found that dHNF4 activity is decreased indERRmutants. Overall, our findings indicate that dERR plays a multifaceted role in the larval fat body to coordinate lipid storage with developmental growth and hint at a conserved mechanism by which ERR and HNF4 homologs coordinately regulate metabolic gene expression
2024-08-02 | GSE273774 | GEO
Project description:Even though the functions of ANGPTL3 in the circulation are relatively well characterized, many mechanistic questions regarding the molecular consequences of ANGPTL3 loss-of-function and protection against cardiovascular disease remain unanswered. To help understant the molecular mechanisms exerted by ANGPTL3 deficiency, we studied the alterations of ANGPTL3 loss-of-function in hepatocytes and plasma lipid molecular species profiles.
2023-04-06 | GSE229133 | GEO
Project description:Purpose: The goal of this study was to evaluate the effect of ANGPTL3 inhibition on liver transcriptomes in LDLR KO mice. Methods: Mice were treated once weekly for 3 weeks with 25mg/kg control mAb or ANGPTL3 mAb. Livers were harvested 6 days after the last mAb treatment. Results: ANGPTL3 inhibition had no major impact on hepatic gene expression.
2020-07-05 | GSE143726 | GEO