The transcription factor cyclic AMP–responsive element–binding protein H regulates triglyceride metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE29643 | GEO | 2011/06/04
SECONDARY ACCESSION(S): PRJNA141223
REPOSITORIES: GEO
Similar Datasets
Project description:Here we report that the transcription factor cyclic AMP–responsive element–binding protein H (CREB-H, encoded by CREB3L3) is required for the maintenance of normal plasma triglyceride concentrations. CREB-H–deficient mice showed hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by lipoprotein lipase (Lpl), partly due to defective expression of the Lpl coactivators Apoc2, Apoa4 and Apoa5 and concurrent augmentation of the Lpl inhibitor Apoc3. We identified multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein in humans with extreme hypertriglyceridemia, implying a crucial role for CREB-H in human triglyceride metabolism. Total RNAs were isolated from the liver of three WT and three Creb3l3 deficient mice after a 24-h fasting. Littermates were used. Gene expression profiles were examined using Illumina WG-6 microarray chips.
2011-06-04 | E-GEOD-29643 | biostudies-arrayexpress
Project description:Sel1L is an adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum-associated degradation (ERAD), but its physiological role in a cell-type-specific manner remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Mechanistically, our data demonstrate a critical requirement of Sel1L for the secretion of lipoprotein lipase (LPL), independently of its role in Hrd1-mediated ERAD and ER homeostasis. Further biochemical analyses revealed that Sel1L physically interacts and stabilizes the LPL maturation complex consisted of LPL and lipase-maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and prone to the formation of protein aggregates, which are degraded by autophagy-mediated degradation. The Sel1L-mediated control of LPL secretion is seen in other LPL-expressing cell types as well such as cardiac muscle and macrophages. Thus, our study reports a novel role of Sel1L in LPL secretion and systemic lipid metabolism. Sel1Lflox/flox mice were crossed with adiponectin promoter driven Cre mice to create adipose tissue-specific Sel1L-/- mice. Male wildtype C57Bl/6 mice and adipose tissue-specific Sel1l-/- mice were fed a high fat diet (Research Diets D12492) for 5 weeks. Adipose tissue was excised and used for microarray analysis.
2015-05-18 | E-GEOD-56918 | biostudies-arrayexpress
Project description:Sel1L is an adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum-associated degradation (ERAD), but its physiological role in a cell-type-specific manner remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Mechanistically, our data demonstrate a critical requirement of Sel1L for the secretion of lipoprotein lipase (LPL), independently of its role in Hrd1-mediated ERAD and ER homeostasis. Further biochemical analyses revealed that Sel1L physically interacts and stabilizes the LPL maturation complex consisted of LPL and lipase-maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and prone to the formation of protein aggregates, which are degraded by autophagy-mediated degradation. The Sel1L-mediated control of LPL secretion is seen in other LPL-expressing cell types as well such as cardiac muscle and macrophages. Thus, our study reports a novel role of Sel1L in LPL secretion and systemic lipid metabolism.
2015-05-18 | GSE56918 | GEO
Project description:High triglycerides can lead to atherosclerotic cardiovascular disease. Long noncoding RNAs (lncRNAs) are currently consider to have vital and wide range of biological functions, but the molecular mechanism underlying TG metabolism remains poorly understood. To identify novel lncRNAs differentially expressed in rat liver with hypertriglyceridemia using transcriptome sequencing and elucidated the function role in TG metabolism. In our study, we identified a novel lncRNA, Lnc19959.2, which was highly expression in rat liver with hypertriglyceridemia. Knockdown of lnc19959.2 has profound TG lowering effects in vitro and vivo. Subsequently genome-wide analysis identified that knockdown of Lnc19959.2 caused deregulation of many genes during TG homeostasis. Further mechanism studies reveal that Lnc19959.2 specifically bound to Purb to up-regulate expression of Apoa4, while bound to hnRNPA2B1 to down-regulate the expression of Cpt1a, Tm7sf2 and Gpam, respectively. In the upstream pathway, palmitate acid up-regulated CCAAT/Enhancer-Binding Protein Beta (Cebpb) facilitates its binding to promoter region of Lnc19959.2, which resulted in significant promotion of lnc19959.2 transcriptional activity. Our findings provide novel insights into transcriptional regulation of TG homeostasis by a novel lncRNA. This newly identified lncRNA could be exploited as novel therapeutic targets for hypertriglyceridemia.
2020-06-08 | GSE137131 | GEO
Project description:High triglycerides can lead to atherosclerotic cardiovascular disease. Long noncoding RNAs (lncRNAs) are currently consider to have vital and wide range of biological functions, but the molecular mechanism underlying TG metabolism remains poorly understood. To identify novel lncRNAs differentially expressed in rat liver with hypertriglyceridemia using transcriptome sequencing and elucidated the function role in TG metabolism. In our study, we identified a novel lncRNA, Lnc19959.2, which was highly expression in rat liver with hypertriglyceridemia. Knockdown of lnc19959.2 has profound TG lowering effects in vitro and vivo. Subsequently genome-wide analysis identified that knockdown of Lnc19959.2 caused deregulation of many genes during TG homeostasis. Further mechanism studies reveal that Lnc19959.2 specifically bound to Purb to up-regulate expression of Apoa4, while bound to hnRNPA2B1 to down-regulate the expression of Cpt1a, Tm7sf2 and Gpam, respectively. In the upstream pathway, palmitate acid up-regulated CCAAT/Enhancer-Binding Protein Beta (Cebpb) facilitates its binding to promoter region of Lnc19959.2, which resulted in significant promotion of lnc19959.2 transcriptional activity. Our findings provide novel insights into transcriptional regulation of TG homeostasis by a novel lncRNA. This newly identified lncRNA could be exploited as novel therapeutic targets for hypertriglyceridemia.
2020-06-08 | GSE137712 | GEO
Project description:High triglycerides can lead to atherosclerotic cardiovascular disease. Long noncoding RNAs (lncRNAs) are currently consider to have vital and wide range of biological functions, but the molecular mechanism underlying TG metabolism remains poorly understood. To identify novel lncRNAs differentially expressed in rat liver with hypertriglyceridemia using transcriptome sequencing and elucidated the function role in TG metabolism. In our study, we identified a novel lncRNA, Lnc19959.2, which was highly expression in rat liver with hypertriglyceridemia. Knockdown of lnc19959.2 has profound TG lowering effects in vitro and vivo. Subsequently genome-wide analysis identified that knockdown of Lnc19959.2 caused deregulation of many genes during TG homeostasis. Further mechanism studies reveal that Lnc19959.2 specifically bound to Purb to up-regulate expression of Apoa4, while bound to hnRNPA2B1 to down-regulate the expression of Cpt1a, Tm7sf2 and Gpam, respectively. In the upstream pathway, palmitate acid up-regulated CCAAT/Enhancer-Binding Protein Beta (Cebpb) facilitates its binding to promoter region of Lnc19959.2, which resulted in significant promotion of lnc19959.2 transcriptional activity. Our findings provide novel insights into transcriptional regulation of TG homeostasis by a novel lncRNA. This newly identified lncRNA could be exploited as novel therapeutic targets for hypertriglyceridemia.
2022-09-11 | GSE137252 | GEO
Project description:Apolipoprotein F (ApoF) modulates lipoprotein metabolism by selectively inhibiting cholesteryl ester transfer protein (CETP) activity on LDL. This ApoF activity requires that it is bound to LDL. How hyperlipidemia alters total plasma ApoF and its binding to LDL are poorly understood. In this study, total ApoF and LDL-bound ApoF were quantified by ELISA. Plasma ApoF is increased 34% in hypercholesterolemic plasma. In hypertriglyceridemic plasma, ApoF was statistically unchanged. However, in donors with combined hypercholesterolemia and hypertriglyceridemia, the elevated triglyceride ameliorated the rise in ApoF caused by hypercholesterolemia alone. Compared to normolipidemic LDL, hypercholesterolemic LDL contained ~2-fold more ApoF per LDL particle, whereas ApoF bound to LDL in hypertriglyceridemia plasma was < 20% of control. To understand the basis for altered association of ApoF with hyperlipidemic LDL, the physiochemical properties of LDL were modified in vitro by CETP ± LCAT activities. The time-dependent change in LDL lipid composition, proteome, core and surface lipid packing, LDL surface charge, and LDL size caused by these factors were compared with the ApoF binding capacity of these LDL. Only LDL particle size correlated with ApoF binding capacity. This positive association between LDL size and ApoF content was confirmed in hyperlipidemic plasmas. Similarly, when in vitro-produced, enlarged LDL with elevated ApoF binding capacity were incubated with LPL to reduce their size, ApoF binding was reduced by 90%. Thus, plasma ApoF levels and the activation status of this ApoF are differentially altered by hypercholesterolemia and hypertriglyceridemia. LDL size is a key determinate of ApoF binding and activation.
2022-02-11 | PXD029713 | Pride
Project description:Lipoprotein lipase (LPL) is an extracellular lipase that preferentially hydrolyses triglycerides in triglyceride-rich lipoproteins within the circulation. LPL expression in macrophages contributes to atherosclerosis. In addition, the hydrolysis products liberated from lipoprotein lipids by LPL causes lipid accumulation and impairs cholesterol efflux ability in macrophages. However, the effects of LPL hydrolysis products in modulating the transcript profiles within macrophages and their roles in foam cell formation are not completely understood. We performed microarray analyses on THP-1 macrophages incubated with LPL hydrolysis products to identify differentially expressed genes.
2017-02-15 | GSE84791 | GEO
Project description:Peroxisome Proliferator-Activated receptor α (PPARα) and cAMP-Responsive Element Binding Protein 3-Like 3 (CREB3L3) are transcription factors involved in the regulation of lipid metabolism in the liver. The aim of the present study was to characterize the interrelationship between PPARα and CREB3L3 in regulating hepatic gene expression. Male wildtype, PPARα-/-, CREB3L3-/- and combined PPARα/CREB3L3-/- mice were subjected to a 16-hour fast or 4 days of ketogenic diet. Whole genome expression analysis was performed on liver samples. Under conditions of overnight fasting, the effects of PPARα ablation and CREB3L3 ablation on plasma triglyceride, plasma β-hydroxybutyrate, and hepatic gene expression were largely disparate, and showed only limited interdependence. Gene and pathway analysis underscored the importance of CREB3L3 in regulating (apo)lipoprotein metabolism, and of PPARα as master regulator of intracellular lipid metabolism. A small number of genes, including Fgf21 and Mfsd2a, were under dual control of PPARα and CREB3L3. By contrast, a strong interaction between PPARα and CREB3L3 ablation was observed during ketogenic diet feeding. Specifically, the pronounced effects of CREB3L3 ablation on liver damage and hepatic gene expression during ketogenic diet were almost completely abolished by the simultaneous ablation of PPARα. Loss of CREB3L3 influenced PPARα signalling in two major ways. Firstly, it reduced expression of PPARα and its target genes involved in fatty acid oxidation and ketogenesis. In stark contrast, the hepatoproliferative function of PPARα was markedly activated by loss of CREB3L3. These data indicate that CREB3L3 ablation uncouples the hepatoproliferative and lipid metabolic effects of PPARα. Overall, except for the shared regulation of a very limited number of genes, the roles of PPARα and CREB3L3 in hepatic lipid metabolism are clearly distinct and are highly dependent on dietary status.
2019-01-23 | GSE121096 | GEO
Project description:The PPAR? activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. After 4 hours fasting, livers were isolated and individual gene arrays were performed.
2010-05-27 | E-GEOD-21211 | biostudies-arrayexpress