ASGR1 Is a Promising Target for Lipid Reduction in Pigs with PON2 As Its Inhibitor
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PROVIDER: PRJNA1119453 | ENA |
REPOSITORIES: ENA
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Project description:Although the role of asialoglycoprotein receptor 1 (ASGR1) in lowering lipid levels is well established, recent studies indicate that ASGR1 inhibition can cause unexpected liver damage in pigs, raising a serious issue about whether ASGR1 can be a good target for treating ASCVD. Here, we utilized the CRISPR/Cas9 system to regenerate ASGR1-knockout pigs, who displayed decreased lipid profiles without observable liver damage, which were confirmed by the lower levels of serum ALT and AST, reduced expression of inflammation markers, and normal histological morphology. Also, we implemented immunoprecipitation combined with mass spectrometry (IP-MS) and discovered that Paraoxonase-2 (PON2) can interact with and significantly degrade ASGR1 in a dose-dependent manner. This degradation led to reduced lipid levels in mice, accompanied by little inflammation. Our study highlights the effectiveness and safety of degrading ASGR1 to reduce lipid levels in pigs and provides a potential inhibitor of ASGR1.
2024-08-16 | GSE268910 | GEO
Project description:A population genetic study identified that the asialoglycoprotein receptor 1 (ASGR1) mutation carriers had significantly lower non-HDL-c levels and reduced risks of cardiovascular diseases. However, the mechanism behind this phenomenon remained unclear. Here, we established Asgr1 knockout mice that represented a plasma lipid profile with significantly lower non-HDL-c and triglyceride caused by decreased secretion and increased uptake of VLDL/LDL. These two phenotypes were linked with the decreased expression of microsomal triglyceride transfer protein (MTTP) and proprotein convertase subtilisin/kexin type 9 (PCSK9), two key target genes of the sterol regulatory element-binding proteins (SREBPs). Furthermore, there were less nSREBPs on account of more SREBPs being trapped in endoplasmic reticulum, which was caused by an increased expression of insulin-induced gene 1 (INSIG1), an anchor of SREBPs. Logically, two rescue experiments were conducted in ASGR1 deficient condition. Both INSIG1 knockdown and ASGR1 rescue independently reversed the ASGR1-mutated phenotypes, restoring the SREBP signaling manifested by improved APOB secretion and reduced LDL uptake. Our observation demonstrated a novel axis of ASGR1-INSIG1-SREBPs regulating lipid hemostasis, and hypomorphic manipulation of ASGR1 leads to significant reduction of lipid content via less nSREBPs. It provides multiple potential targets, including ASGR, for lipid-lowering drug development.
2021-12-31 | GSE178370 | GEO
Project description:Hypomorphic ASGR1 Modulates Lipid Homeostasis via SREBPs Network
| PRJNA738702 | ENA
Project description:In the last 20 years, there has been significant research towards defining the genetic basis of lipid metabolism and meat quality related traits in pigs. Nowadays, the study of the transcriptome and its regulatory mechanisms allows going far beyond in the genetic dissection of these complex traits. In present study, a genome-wide eQTL scan aiming to detect pig genome regions regulating levels of skeletal muscle mRNA expression has been performed. This study has been conducted on a commercial Duroc population where a number of QTL for muscle fat deposition and fatty acid composition had been detected. GeneChip Porcine Genome® arrays (Affymetrix) were used to determine the gene expression levels of gluteus medius samples from 105 Duroc pigs belonging to two groups with divergent phenotypes for fatness traits. This experimental design aimed to favour detection of eQTL affecting genes related to lipid metabolism and meat quality traits. The whole genome scan with a panel of 110 microsatellites allowed us detecting 613 genome-wide significant eQTL unequally distributed across the pig genome, SSC5 and SSC3 harbouring the highest number of eQTL. Moreover, 11 genome regions with eQTL affecting the expression levels of a high number of genes (eQTL hot spots) have been described. After mapping target probes and discarding low quality probes, a total of 59 cis- and 396 trans-acting eQTL were retained for further analyses. The functional classification showed that lipid-related GO terms were not the most enriched by the list of eQTL-regulated genes. However, a number of regulated genes functionally related to lipid metabolism and fat deposition traits were identified, and their functional relationship with these phenotypes were further investigated. With this purpose, eQTL results were integrated with 1) QTL linkage maps and 2) correlation data between phenotypes and gene expression levels. As a result, a comprehensive list of 29 positional and functional candidate genes was elaborated. These results represent a valuable contribution to the comprehension of genetic regulation of skeletal muscle individual gene expression in swine species, and a first step towards disentangling gene networks and molecular mechanisms involved in lipid metabolism and meat quality traits. 105 gluteus medius samples from 105 animals belonging to two groups of 53 and 52 animals each: HIGH group had higher carcass, plasma and muscle fat content; LOW group had lower carcass, plasma and muscle fat content
2010-12-16 | E-GEOD-26091 | biostudies-arrayexpress
Project description:Feed efficiency (FE) is an indicator of efficiency in converting energy, attained from macronutrient ingestion, into tissue. Adipose tissue, besides being a master regulator of systemic lipid storage, is also an active endocrine organ that communicates with skeletal muscle, liver and brain to influence appetite, lipid & glucose metabolism and energy homeostasis. Adipose tissue is hypothesised to play a vital part in regulation of FE. The objective of the present study was to sequence the subcutaneous adipose tissue transcriptome in FE-divergent pigs (n=16) and identify relevant biological processes underpinning observed differences in FE.
2018-11-14 | E-MTAB-6255 | biostudies-arrayexpress
Project description:Purpose: Obesity and dyslipidemia are associated with increased risk of renal disease.Testosterone deficiency aggravated high-fat diet-induced obesity and hypercholeterolemia. However,whether testosterone deficiency or testosterone deficiency-induced dyslipidemia aggravate the progression of renal disease is not clear. To gain insight into the role of testosterone in modulating renal lipid metabolism, we profiled renal gene expression by RNA-Seq in HFC-fed intact male pigs (IM), castrated male pigs (CM), and castrated male pigs with testosterone replacement (CMT). Methods: Sexually mature male miniature pigs were either surgical castrated or sham-operated, and castrated with testosterone replacement. We administrated to pigs a high-fat and high-cholesterol (HFC) diet for twelve weeks. RNA-Seq was employed to profile renal gene expression in pigs with different testosterone levels. Conclusions: This study demonstrated that testosterone deficiency aggravated renal lipid accumulation in pigs fed an HFC diet and that these effects could be reversed by testosterone replacement therapy. Impaired metabolic processes, bile acid secretion,estrogen signaling pathway and enhanced triglyceride synthesis may contribute to the increased renal lipid accumulation induced by testosterone deficiency and an HFC diet.
2023-01-17 | GSE125343 | GEO
Project description:In the last 20 years, there has been significant research towards defining the genetic basis of lipid metabolism and meat quality related traits in pigs. Nowadays, the study of the transcriptome and its regulatory mechanisms allows going far beyond in the genetic dissection of these complex traits. In present study, a genome-wide eQTL scan aiming to detect pig genome regions regulating levels of skeletal muscle mRNA expression has been performed. This study has been conducted on a commercial Duroc population where a number of QTL for muscle fat deposition and fatty acid composition had been detected. GeneChip Porcine Genome® arrays (Affymetrix) were used to determine the gene expression levels of gluteus medius samples from 105 Duroc pigs belonging to two groups with divergent phenotypes for fatness traits. This experimental design aimed to favour detection of eQTL affecting genes related to lipid metabolism and meat quality traits. The whole genome scan with a panel of 110 microsatellites allowed us detecting 613 genome-wide significant eQTL unequally distributed across the pig genome, SSC5 and SSC3 harbouring the highest number of eQTL. Moreover, 11 genome regions with eQTL affecting the expression levels of a high number of genes (eQTL hot spots) have been described. After mapping target probes and discarding low quality probes, a total of 59 cis- and 396 trans-acting eQTL were retained for further analyses. The functional classification showed that lipid-related GO terms were not the most enriched by the list of eQTL-regulated genes. However, a number of regulated genes functionally related to lipid metabolism and fat deposition traits were identified, and their functional relationship with these phenotypes were further investigated. With this purpose, eQTL results were integrated with 1) QTL linkage maps and 2) correlation data between phenotypes and gene expression levels. As a result, a comprehensive list of 29 positional and functional candidate genes was elaborated. These results represent a valuable contribution to the comprehension of genetic regulation of skeletal muscle individual gene expression in swine species, and a first step towards disentangling gene networks and molecular mechanisms involved in lipid metabolism and meat quality traits.
2010-12-16 | GSE26091 | GEO
Project description:A Promising Natural G6PD Inhibitor for Potential Therapeutic Strategies in DLBCL
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Project description:Differences in adipose tissue deposition and properties between pig male sex categories, i.e., entire male, immunocastrated and surgically castrated pigs are relatively well characterized, whereas the underlying genetic mechanisms are still not fully understood. To gain the knowledge about the genetic regulation of the differences in adipose tissue deposition, RNA-sequencing approach was used. A total of 83 differentially expressed genes were identified between entire male and immunocastrated pigs, 15 between immunocastrated and surgically castrated pigs and 48 between entire male and surgically castrated pigs by RNA-sequencing of the subcutaneous adipose tissue. Comparing entire male with immunocastrated or surgically castrated pigs, upregulated genes related to extracellular matrix dynamics, and downregulated genes involved in the control of lipid and carbohydrate metabolism were determinated. Moreover, differential gene expression in general indicated a high similarity between immunocastrated and surgically castrated pigs in contrast to entire males, except for several heat shock protein genes which were upregulated in entire male and immunocastrated pigs compared with surgically castrated pigs.
2021-03-03 | GSE164391 | GEO
Project description:Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Lipid reduction through cytoplasmic lipolysis might adversely worsen steatohepatitis, however, the effect of autophagic lipolysis, lipophagy, remains obscure. We engineered the adaptor protein to induce lipophagy with lipid droplet targeting signal and modified LC3 interacting region. Activating hepatocyte lipophagy obviously mitigated both steatosis and NASH pathology. Mechanistically, lipophagy promoted the excretion of lipid from liver via lysosomal exocytosis and attenuated harmful accumulation of nonesterified fatty acid. This exocytosis was dependent on Ca2+ signal unlike the lysosomal dysfunction-related exocytosis. High content compound screening identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin inhibited the transition to steatohepatitis in mice fed high fat with low methionine low choline diet. Given all these data, activating lipophagy may be a promising therapeutic approach to prevent NASH progression.
2023-05-15 | GSE185911 | GEO