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Resolvins activate inflammation-resolution programs: a systems approach to resolution
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Abstracts / Chemistry and Physics of Lipids 160S (2009) S1–S17
and mass spectrometry (MS). Raman studies of HSC incubated with or without deuterated fatty acids show that HSC display a heterogeneous LD pattern, both in size and retinyl ester content. However, in individual stellate cells a uniform LD lipid profile is observed with most LDs localized perinuclearly. Upon activation of the HSC the LDs reduce in size and partly migrate to cellular extensions. Furthermore their lipid composition changes as judged from shifts in their Raman spectrum and HPLC–MS analysis. After activation, HSC show a decrease in the main retinoid species, that is accompanied by an increase in cholesterolesters and polyunsaturated fatty acid-containing triacylglycerol species.
Session 4: Eicosanoids and biological signaling
doi:10.1016/j.chemphyslip.2009.06.109
We focused on gaining a more complete understanding of the cellular and molecular events that govern natural resolution of acute inflammatory responses in self-limited inflammation with mammalian systems. Using a systems approach with resolving exudates to track tissue events, cell traffic and identification of mediators, we identified novel families of lipid-derived mediators, coined the resolvins and protectins in resolving exudates that control both the duration and magnitude of acute inflammation. These endogenous resolution circuits provide new avenues to probe the molecular basis of many widely occurring diseases associated with uncontrolled inflammation (Serhan et al., 2008). This presentation focuses on our recent advances on the biosynthesis and functions of this novel genus of specialized pro-resolving mediators (SPM). These previously unknown families of local chemical mediators were originally identified in murine exudates captured during the natural self-limited phase. SPM include 3 chemical mediator families termed resolvins, protectins and the most recent addition, maresins, which are biosynthesized from the essential omega-3 fatty acids and possess potent multi-prong anti-inflammatory, pro-resolving and anti-microbial actions. We recently reported microfluidics to monitor single cell actions of SPM as functional metabolomics in ∼1 l within 5 min from blood. This new evidence changes the >100 years old concept that resolution of acute inflammation is a passive process. Together these findings indicate that defective and/or blocking of natural resolution pathways may underlie many prevalent diseases associated with uncontrolled local inflammation and the potential for resolution-based therapeutics.
SO 9 Improved lipid metabolism and reduced fat deposition in a mouse model of diet-induced obesity (DIO) with a new dual PPAR␣/␥ ligand F. Gilardi 1,∗ , N. Mitro 1 , M. Giudici 1 , G. Cermenati 1 , U. Guerrini 1 , E. Tremoli 1 , G. Rando 1 , A. Maggi 1 , F. Loiodice 2 , G. Fracchiolla 2 , A. Laghezza 2 , G. Pochetti 3 , A. Lavecchia 4 , E. De Fabiani 1 , D. Caruso 1 , M. Crestani 1 1
Department of Pharmacological Sciences, University of Milano, Italy University of Bari, Italy 3 CNR, Montelibretti, Roma, Italy 4 University of Napoli, Italy 2
Peroxisome proliferator-activated receptors (PPARs) are liganddependent transcription factors regulating lipid and glucose metabolism. Ongoing drug discovery programs aim at developing dual PPAR␣/␥ agonists devoid of the side effects of the marketed antidiabetic agents thiazolidinediones and the dual-agonists glitazars. We recently described a new dual PPAR␣/␥ ligand, LT175, with a partial agonist profile against PPAR␣/␥ and interacting with a new region of the PPAR␥-LBD (JMC, 2008, 51:7768). Here we show that LT175 activates the PPAR␥-dependent program of differentiation in adipocyte cultures, without inducing the severe accumulation of lipids observed with rosiglitazone, suggesting that this molecule may have lower adipogenic activity. Consistent with this hypothesis, in vivo administration of LT175 to DIO mice decreases body weight and white adipose tissue mass, as assessed by Magnetic Resonance Imaging. Furthermore LT175 significantly reduces plasma glucose, insulin, NEFAs, triglycerides and cholesterol and increases adiponectin levels. The OGTT and ITT show that the compound improves glucose homeostasis and insulin sensitivity. Finally the in vivo analysis performed in a PPRE-luc reporter mouse demonstrates that LT175 rapidly activates PPAR-dependent transcription. This was confirmed by determining the expression of PPAR target genes in the liver, white and brown adipose tissue and skeletal muscle by Q-PCR. In conclusion, our results describe a new PPAR ligand modulating lipid and glucose metabolism without adipogenic activity, which may be used as a scaffold to design new molecules with improved pharmacological profile for the treatment of metabolic disorders. Acknowledgement: Funded by Italian Ministry of University to MC, PRIN and Giovanni Armenise-Harvard Foundation to NM). doi:10.1016/j.chemphyslip.2009.06.110
PL 14 Resolvins activate inflammation-resolution programs: a systems approach to resolution Charles N. Serhan Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, BWH and Harvard Medical School, Boston, MA, USA
Acknowledgement: Funded CNS acknowledges support of NIH P50-DE016191, GM038765, DK074448. Reference Serhan, et al., 2008. Nat. Rev. Immunol..
doi:10.1016/j.chemphyslip.2009.06.111 PL 15 Lipid mediators and glycerophospholipid metabolism Takao Shimizu Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan Prostaglandins (PG), leukotrienes (LT), lysophosphatidic acid (LPA), platelet-activating factor (PAF) etc. are collectively termed lipid mediators. They exert a wide variety of biological actions through cognate G-protein coupled receptors. siRNA experiments and KO mouse studies have revealed critical roles of lipid mediators in both physiology and pathology. Most lipid mediators are produced by enzymic cascade initiated by the action of several isozymes of cytosolic phospholipase A2, a Ca-dependent
Abstracts / Chemistry and Physics of Lipids 160S (2009) S1–S17
and mass spectrometry (MS). Raman studies of HSC incubated with or without deuterated fatty acids show that HSC display a heterogeneous LD pattern, both in size and retinyl ester content. However, in individual stellate cells a uniform LD lipid profile is observed with most LDs localized perinuclearly. Upon activation of the HSC the LDs reduce in size and partly migrate to cellular extensions. Furthermore their lipid composition changes as judged from shifts in their Raman spectrum and HPLC–MS analysis. After activation, HSC show a decrease in the main retinoid species, that is accompanied by an increase in cholesterolesters and polyunsaturated fatty acid-containing triacylglycerol species.
Session 4: Eicosanoids and biological signaling
doi:10.1016/j.chemphyslip.2009.06.109
We focused on gaining a more complete understanding of the cellular and molecular events that govern natural resolution of acute inflammatory responses in self-limited inflammation with mammalian systems. Using a systems approach with resolving exudates to track tissue events, cell traffic and identification of mediators, we identified novel families of lipid-derived mediators, coined the resolvins and protectins in resolving exudates that control both the duration and magnitude of acute inflammation. These endogenous resolution circuits provide new avenues to probe the molecular basis of many widely occurring diseases associated with uncontrolled inflammation (Serhan et al., 2008). This presentation focuses on our recent advances on the biosynthesis and functions of this novel genus of specialized pro-resolving mediators (SPM). These previously unknown families of local chemical mediators were originally identified in murine exudates captured during the natural self-limited phase. SPM include 3 chemical mediator families termed resolvins, protectins and the most recent addition, maresins, which are biosynthesized from the essential omega-3 fatty acids and possess potent multi-prong anti-inflammatory, pro-resolving and anti-microbial actions. We recently reported microfluidics to monitor single cell actions of SPM as functional metabolomics in ∼1 l within 5 min from blood. This new evidence changes the >100 years old concept that resolution of acute inflammation is a passive process. Together these findings indicate that defective and/or blocking of natural resolution pathways may underlie many prevalent diseases associated with uncontrolled local inflammation and the potential for resolution-based therapeutics.
SO 9 Improved lipid metabolism and reduced fat deposition in a mouse model of diet-induced obesity (DIO) with a new dual PPAR␣/␥ ligand F. Gilardi 1,∗ , N. Mitro 1 , M. Giudici 1 , G. Cermenati 1 , U. Guerrini 1 , E. Tremoli 1 , G. Rando 1 , A. Maggi 1 , F. Loiodice 2 , G. Fracchiolla 2 , A. Laghezza 2 , G. Pochetti 3 , A. Lavecchia 4 , E. De Fabiani 1 , D. Caruso 1 , M. Crestani 1 1
Department of Pharmacological Sciences, University of Milano, Italy University of Bari, Italy 3 CNR, Montelibretti, Roma, Italy 4 University of Napoli, Italy 2
Peroxisome proliferator-activated receptors (PPARs) are liganddependent transcription factors regulating lipid and glucose metabolism. Ongoing drug discovery programs aim at developing dual PPAR␣/␥ agonists devoid of the side effects of the marketed antidiabetic agents thiazolidinediones and the dual-agonists glitazars. We recently described a new dual PPAR␣/␥ ligand, LT175, with a partial agonist profile against PPAR␣/␥ and interacting with a new region of the PPAR␥-LBD (JMC, 2008, 51:7768). Here we show that LT175 activates the PPAR␥-dependent program of differentiation in adipocyte cultures, without inducing the severe accumulation of lipids observed with rosiglitazone, suggesting that this molecule may have lower adipogenic activity. Consistent with this hypothesis, in vivo administration of LT175 to DIO mice decreases body weight and white adipose tissue mass, as assessed by Magnetic Resonance Imaging. Furthermore LT175 significantly reduces plasma glucose, insulin, NEFAs, triglycerides and cholesterol and increases adiponectin levels. The OGTT and ITT show that the compound improves glucose homeostasis and insulin sensitivity. Finally the in vivo analysis performed in a PPRE-luc reporter mouse demonstrates that LT175 rapidly activates PPAR-dependent transcription. This was confirmed by determining the expression of PPAR target genes in the liver, white and brown adipose tissue and skeletal muscle by Q-PCR. In conclusion, our results describe a new PPAR ligand modulating lipid and glucose metabolism without adipogenic activity, which may be used as a scaffold to design new molecules with improved pharmacological profile for the treatment of metabolic disorders. Acknowledgement: Funded by Italian Ministry of University to MC, PRIN and Giovanni Armenise-Harvard Foundation to NM). doi:10.1016/j.chemphyslip.2009.06.110
PL 14 Resolvins activate inflammation-resolution programs: a systems approach to resolution Charles N. Serhan Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, BWH and Harvard Medical School, Boston, MA, USA
Acknowledgement: Funded CNS acknowledges support of NIH P50-DE016191, GM038765, DK074448. Reference Serhan, et al., 2008. Nat. Rev. Immunol..
doi:10.1016/j.chemphyslip.2009.06.111 PL 15 Lipid mediators and glycerophospholipid metabolism Takao Shimizu Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan Prostaglandins (PG), leukotrienes (LT), lysophosphatidic acid (LPA), platelet-activating factor (PAF) etc. are collectively termed lipid mediators. They exert a wide variety of biological actions through cognate G-protein coupled receptors. siRNA experiments and KO mouse studies have revealed critical roles of lipid mediators in both physiology and pathology. Most lipid mediators are produced by enzymic cascade initiated by the action of several isozymes of cytosolic phospholipase A2, a Ca-dependent