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Inhibition of adipose triglyceride lipase alleviates non-alcoholic steatohepatitis in diabetic mice via impaired PPARa signalling favouring hydrophilic bile acid composition

ABSTRACT: Inhibition of adipose triglyceride lipase alleviates non-alcoholic steatohepatitis in diabetic mice via impaired PPARa signalling favouring hydrophilic bile acid composition

PROVIDER: PRJNA992503 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25194567.fastq.gz	Fastqsanger.gz
	SRR25194568.fastq.gz	Fastqsanger.gz
	SRR25194569.fastq.gz	Fastqsanger.gz
	SRR25194570.fastq.gz	Fastqsanger.gz
	SRR25194571.fastq.gz	Fastqsanger.gz

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Inhibition of adipose triglyceride lipase alleviates non-alcoholic steatohepatitis in diabetic mice via impaired PPARa signalling favouring hydrophilic bile acid composition

Project description:Inhibition of adipocyte triglyceride lipase (ATGL/PNPLA2) activity in insulin resistance and non-alcoholic fatty liver disease is an attractive therapeutic target. This study evaluated the impact of Atglistatin-mediated ATGL inhibition on non-alcoholic steatohepatitis (NASH) development in diabetic and hyperlipidaemic mice. Streptozotocin-injected male mice were fed an HFD to induce NASH. We analysed liver histology, hepatic lipid content, immunohistochemistry, RNA sequencing, and serum biochemistry. Mechanistically, we treated Caco2 cells, human primary ileum-derived organoids, and HepG2 ATGL KD cells with the novel human ATGL inhibitor NG-497 and WY14643. Atglistatin reduced body and liver weights, total liver lipid content, and improved blood sugar levels consistent with improved liver enzymes, histological liver injury, and NAFLD activity scores. Mechanistically, Atglistatin reduced Cpt1a and Abca1, suggesting impaired Ppara signalling that favours hydrophilic bile acids (BA) synthesis since Cyp7a1, Cyp27a1, and Cyp2c70 were increased while Cyp8b1 was reduced. Accordingly, Intestinal lipid transporters, Abca1 and Cd36, were reduced, consistent with the reduction of liver TAG species, mostly linoleic acids. We used human-specific ATGL inhibitor NG-497 to validate the mouse findings. The NG-497-treated human primary ileum organoids and Caco2 cells showed reduced ATGL, ABCA1, FATP5, CD36, and MTTP. PPARa signalling was impaired in the ileum organoids and HepG2 treated with NG-497 and in HepG2 ATGL KD since PPARa, CPT1a, AOX, ABCA1, and CYP8B1 were reduced, and CYP7A1 increased. Inhibition of ATGL activity reduces the availability of ligands for Ppara activation leading to impaired Ppara signalling, which translate into hydrophilic BA that interferes with dietary lipid absorption, improving metabolic disturbances. The validation with the NG-497 should open a new clinical avenue for NAFLD clinical trial and treatment.

2024-11-01 | GSE236832 | GEO

Loss of adipose triglyceride lipase aids cancer growth in 3D

Project description:Shotgun proteomic analysis of 3D-grown or on CAM-assay grown lung cancer cells lacking or expressing the major triglyceride lipase adipose triglyceride lipase (ATGL)

2021-05-21 | PXD021105 | Pride

Non-remnant triglyceride-rich lipoproteins due to lipoprotein lipase deficiency increase atherosclerosis in mice

Project description:Although hypertriglyceridemia and postprandial lipemia associate with greater atherosclerosis, partially metabolized triglyceride-rich lipoproteins termed remnants rather than nascent lipoproteins have been implicated as the culprits. Whether chylomicrons are inherently atherogenic remains unclear. To test whether increased levels of nascent triglyceride-rich lipoproteins (TRLs) in the absence of markedly reduced LDL-C levels contribute to atherosclerosis, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl-/-) and LDLR knockdown (Ldlrkd) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl-/-/Ldlrkd mice than control Ldlrkd mice. Aorta from hypertriglyceridemic mice had changes in the transcriptomes of endothelial cells, macrophages, and smooth muscle cells indicating vascular inflammation. Our data show that intact TRLs contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease, and prove that non-remnant TRLs are not benign.

2025-09-15 | GSE307653 | GEO

Non-remnant triglyceride-rich lipoproteins due to lipoprotein lipase deficiency increase atherosclerosis in mice

Project description:Non-remnant triglyceride-rich lipoproteins due to lipoprotein lipase deficiency increase atherosclerosis in mice

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Transcriptomic analysis of tissues and embryos from control and triglyceride lipase 2 (TL2)-deficient Anopheles gambiae females.

Project description:We explored the role of triglyceride (TAG) mobilization in the reproductive success of female Anopheles gambiae after a blood meal. Silencing triglyceride lipase 2 (TL2) in An. gambiae reduced egg production and abrogates fertility. Embryos from AgTL2-depleted females develop normally but fail to hatch and are characterized by reduced levels of lipids and key metabolites, including carbohydrates, Tricarboxylic acid (TCA) intermediates, paralleled by increased levels of purine and pyrimidine breakdown products, signifying possible cellular death. To obtain a better understanding of the mechanism underlying embryonic lethality in AgTL2-deficient females, we generated RNA-Seq datasets of tissues and embryos from control and TL2-knockdown females at different time points after blood feeding (for tissues) and oviposition. These analyses revealed that while at earlier time points there is almost no difference, transcriptomic profiles at the later time point of 38 hours after laying were profoundly distinct between both groups. Specifically, pathways involved in neuropeptide signaling, G-protein coupled receptor signaling, and eclosion hormone synthesis were repressed in TL2-knockdown condition while hallmarks of cellular stress were significantly up-regulated. More importantly, pathways involved in de novo lipid synthesis and transport were significantly up-regulated, possibly to compensate for reduced levels of maternally inherited lipids.

2024-11-08 | GSE263712 | GEO

The transcription factor cyclic AMP–responsive element–binding protein H regulates triglyceride metabolism

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

The ER-Associated Degradation Adapter Protein Sel1L Regulates Triglyceride Metabolism via Lipoprotein Lipase

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

The transcription factor cyclic AMP–responsive element–binding protein H regulates triglyceride metabolism

2011-06-04 | GSE29643 | GEO

The ER-Associated Degradation Adapter Protein Sel1L Regulates Triglyceride Metabolism via Lipoprotein Lipase

2015-05-18 | GSE56918 | GEO

Gene expression analysis of human macrophages exposed to lipoprotein lipase hydrolysis products

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

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