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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression of Splicing Factor Genes is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis

ABSTRACT: Alternative mRNA splicing provides transcript diversity and has been proposed to contribute to several human diseases. Here, we demonstrate that expression of genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. To determine the metabolic impact of reduced splicing factor expression, we further evaluated the splicing factor, SFRS10, identified as down-regulated in obese human liver and skeletal muscle and in high fat fed rodents. siRNA-mediated reductions in SFRS10 expression induced lipogenesis and lipid accumulation in cultured hepatocytes. Moreover, SFRS10 heterozygous mice have both increased hepatic lipogenic gene expression and hypertriglyceridemia. We also demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10, with reduced SFRS10 levels favoring the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished the lipogenic effects of decreased SFRS10 expression. Together, our results indicate reduced expression of SFRS10 alters LPIN1 splicing and induces lipogenesis, demonstrating that reduced splicing factor expression observed in human tissues may contribute to metabolic phenotypes associated with human obesity. Skeletal muscle samples were obtained from 10 lean control subjects and 7 obese subjects with either IGT or DM2 undergoing elective cholecystectomy. Data for liver samples presented in the same manuscript are available at GEO GSE15653. In this analysis RNA was isolated for cRNA preparation and hybridized to Affymetrix Human Genome U133 Plus 2.0 microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Mary Elizabeth Patti

PROVIDER: E-GEOD-22435 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression of Splicing Factor Genes is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis

Project description:Alternative mRNA splicing provides transcript diversity and has been proposed to contribute to several human diseases. Here, we demonstrate that expression of genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. To determine the metabolic impact of reduced splicing factor expression, we further evaluated the splicing factor, SFRS10, identified as down-regulated in obese human liver and skeletal muscle and in high fat fed rodents. siRNA-mediated reductions in SFRS10 expression induced lipogenesis and lipid accumulation in cultured hepatocytes. Moreover, SFRS10 heterozygous mice have both increased hepatic lipogenic gene expression and hypertriglyceridemia. We also demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10, with reduced SFRS10 levels favoring the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished the lipogenic effects of decreased SFRS10 expression. Together, our results indicate reduced expression of SFRS10 alters LPIN1 splicing and induces lipogenesis, demonstrating that reduced splicing factor expression observed in human tissues may contribute to metabolic phenotypes associated with human obesity.

2011-08-03 | GSE22435 | GEO

Lipin 1 regulates mRNA splicing in fasting and feeding in mouse liver

Project description:The lipin phosphatidate phosphatase (PAP) enzymes (lipin 1, lipin 2, and lipin 3) catalyze a step in triglyceride and phospholipid biosynthesis, and genetic lipin deficiencies cause human disease that is triggered by metabolic stress, such as fasting. We assessed the protein interactome of lipins 1, 2, and 3 in hepatocytes, and identified unique protein associations between lipin 1 and U2 mRNA spliceosome components. Lpin1–/– mouse liver exhibited aberrant mRNA splicing in the fasted state, including mRNAs involved in mRNA processing and liver maturation. Aberrant splicing could be induced in cultured hepatocytes by lipin 1 knockdown or elevated phosphatidic acid levels, suggesting a role for lipin 1 PAP activity in splicing fidelity. Refeeding Lpin1–/– animals after fasting largely restored mRNA splicing fidelity. Reduced levels of ESRP2 splicing factor exclusively in the fasted state of Lpin1–/– liver was associated with widespread aberrant exon inclusion. These findings connect lipid homeostasis with mRNA splicing, and identify aberrant mRNA splicing in lipin 1 deficiency as a potential contributor to disease symptoms triggered by fasting.

2021-09-15 | GSE160984 | GEO

Intestinal FGF15/19 physiologically represses hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A

Project description:Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity. Fibroblast Growth Factor-19 (FGF19, mouse FGF15) is a late fed-state gut hormone that decreases hepatic lipid levels by unclear mechanisms. We examined whether FGF15/19 and FGF15/19-activated Small Heterodimer Partner (SHP/NR0B2) have a role in transcriptional repression of lipogenesis. Comparative genomic analyses reveal that most of the SHP cistrome, including lipogenic genes repressed by FGF19, have overlapping CpG islands. FGF19 treatment or SHP overexpression in mice inhibits lipogenesis in a DNA methyltransferase-3a (DNMT3A)-dependent manner. FGF19-mediated activation of SHP via phosphorylation recruits DNMT3A to lipogenic genes, leading to DNA methylation and gene repression. In non-alcoholic fatty liver disease (NAFLD) patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at lipogenic genes are low, with elevated gene expression. These results demonstrate that FGF15/19 represses hepatic lipogenesis by activating SHP and DNMT3A physiologically, which is likely dysregulated in NAFLD.

2020-09-23 | GSE158359 | GEO

Gene Expression Profiles of Nondiabetic and Diabetic Obese Mice--Adipose tissue, Liver, Muscle and Islets

Project description:Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes. Diabetes 52:688–700, 2003 Keywords: Genetic modifications

2005-07-12 | GSE2899 | GEO

Mouse Liver LC-MS/MS LNA miR-676 treated dbdb mice

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2017-11-14 | PXD006573 | Pride

Transcription profiling of mouse LXRalpha null, LXRbeta null mutants reveals liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRalpha (NR1H3) and LXRbeta (NR1H2) subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRalpha and LXRbeta knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRalpha KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRbeta KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRalpha KO mice, but not LXRbeta KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRbeta in skeletal muscle.

2009-10-01 | E-MTAB-61 | biostudies-arrayexpress

Transcription profiling of adipose tissue, liver, skeletal muscle, and pancreatic islets from nondiabetic and diabetic obese mice to understand susceptibility to diabetes.

2007-08-31 | E-GEOD-2899 | biostudies-arrayexpress

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy

Project description:As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR-mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.

2019-01-07 | MTBLS750 | MetaboLights

Expression data from livers of high fat fed rats treated with ACC inhibitor PF-04923503

Project description:Fundamental alterations in lipid metabolism including increased rates of de novo lipogenesis (DNL), reduced fatty acid oxidation (FAOX) and ectopic lipid accumulation in skeletal muscle and liver are characteristic of type 2 diabetes mellitus (T2DM) and have been hypothesized to directly contribute to the molecular pathogenesis of the disease. Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, the rate limiting substrate for DML and key regulator of FAOX. ACC inhibitors have the potential to pharmacologically rebalance these metabolic alterations. In the present study, PF-04923503, a potent dual ACC1/ACC2 inhibitor with properties optimized for in vivo studies, suppressed levels of malonyl-CoA in primary hepatocytes, rat skeletal muscle ex vivo, as well as rat liver and skeletal muscle in vivo. This impact on malonyl-CoA was directly correlated (r2>0.9) with reduced hepatic DNL and inversely correlated with incresed rates of FAOX (r2>0.9). The pharmacological eccfect of PF-04923503 persisted with chronic treatment. High-fat fed rats treated with PF-04923503 for six weeks showed dose-dependent reductions in skeletal muscle and liver lipid accumulation. These changes correlated directly with markers for improved insulin sensitization. However, liver gene expression indicates that pharmacological inhibition results in compensation by up-regualtion of genes involved with DNL. These results suggest that pharmacological inhibition of ACC may have utility to help rebalance metabolic abnormalities in T2DM and improve insulin sensitivity. Differential gene expression was assessed by Affymetrix microarray experiments for 15 liver samples across 3 pharmacological treatment groups (vehicle control 0.5% methylcellulose had 5 samples, PF-04923503 10mpk had 5 samples, PF-04923503 30mpk had 5 samples)

2011-06-30 | E-GEOD-28058 | biostudies-arrayexpress

Liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRM-NM-1 and LXRM-NM-2 subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRM-NM-1 and LXRM-NM-2 knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRM-NM-1 KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRM-NM-2 KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRM-NM-1 KO mice, but not LXRM-NM-2 KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRM-NM-2 in skeletal muscle. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRa and LXRb knockout (KO) mice were established. Sixteen samples were examined. Half the samples were treated with the unselective LXR agonist T0901317.

2010-03-30 | E-GEOD-13192 | biostudies-arrayexpress

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