Dataset Information

Role of caspase-1 in regulation of triglyceride metabolism.

ABSTRACT: Caspase-1 is a cysteine protease that can be activated by both endogenous and exogenous inflammatory stimuli and has been shown to have important functions in processes as diverse as proteolytic activation of cytokines, cell death, and membrane repair. Caspase-1-dependent production of the inflammatory cytokines IL-1 and IL-18 has also been implicated in the regulation of appetite, body weight, glucose homeostasis, and lipid metabolism. Consistent with the emerging views of caspase-1 in metabolic regulation, we find that caspase-1-deficient mice have dramatically accelerated triglyceride clearance, without alteration in lipid production or absorption, and resultant decrease in steady-state circulating triglyceride and fatty acid levels. Surprisingly, this effect is independent of IL-1-family signaling, supporting the concept that caspase-1 influences lipid metabolism through multiple mechanisms, not limited to cytokines.

SUBMITTER: Kotas ME

PROVIDER: S-EPMC3607017 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Role of caspase-1 in regulation of triglyceride metabolism.

Kotas Maya E ME Jurczak Michael J MJ Annicelli Charles C Gillum Matthew P MP Cline Gary W GW Shulman Gerald I GI Medzhitov Ruslan R

Proceedings of the National Academy of Sciences of the United States of America 20130304 12

Caspase-1 is a cysteine protease that can be activated by both endogenous and exogenous inflammatory stimuli and has been shown to have important functions in processes as diverse as proteolytic activation of cytokines, cell death, and membrane repair. Caspase-1-dependent production of the inflammatory cytokines IL-1 and IL-18 has also been implicated in the regulation of appetite, body weight, glucose homeostasis, and lipid metabolism. Consistent with the emerging views of caspase-1 in metaboli ...[more]

PMID: 23487794

Similar Datasets

Project description:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.

Project description:The number of circulating endothelial progenitor cells (EPCs) predicts future development of atherosclerotic cardiovascular disease (ASCVD) and is reduced in patients with type 2 diabetes (T2DM) or impaired glucose tolerance (IGT). Recent studies revealed the contribution of tight control of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), as well as fatty acid oxidation in the regulation of stem cell behavior. In this study, we show that how dysregulated glucose and triglyceride metabolism in T2DM/IGT affects the homeostasis of EPCs, i.e. bone marrow stem/progenitor cells (BMSCs). In our clinical study, consistent with previous reports, the patients with IGT or T2DM showed reduced level of circulating EPCs, as compared normal glucose tolerance. On the other hand, fasting or postprandial hypertriglyceridemia (hTG) itself did not affect the level of circulating EPCs. However, further analysis using single and multiple regression analyses strongly suggested that, in the presence of postprandial hTG, postprandial hyperglycemia exerts devastating effect on EPC homeostasis. We therefore carried out the proof of concept study in mice. Our experimental study revealed that repetitive glucose+lipid (G+L) spikes, but not repetitive glucose (G) spikes or lipid (L) spikes, rapidly upregulated p53 in BMSCs and induced premature aging phenotype of bone marrow cells, i.e. the impairment of BMSC quiescence and function, and myeloid-biased differentiation. Subsequent analysis implicated that p53-mediated augmentation of mitochondrial OXPHOS plays pivotal role for the impairment of BMSC quiescence and function. On the other hand, it is still not clear how repetitive G+L injection induced myeloid-biased differentiation. Because cell-fate decisions are executed by transcription factors in response to extracellular signals, and the best-known function of p53 is as a transcription factor, we asked to what extent repetitive glucose spikes and repetitive glucose+TG spikes affect transcriptional regulation in LSK cells.

Dataset Information

Role of caspase-1 in regulation of triglyceride metabolism.

Publications

Role of caspase-1 in regulation of triglyceride metabolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure