Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

Meana, Clara; Peña, Lucía; Lordén, Gema; Esquinas, Esperanza; Guijas, Carlos; Valdearcos, Martín; Balsinde, Jesús; Balboa, Marı́a A.

doi:10.4049/jimmunol.1400238

Cited by 47 publications

(106 citation statements)

References 42 publications

(42 reference statements)

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“…We propose that the sustained production of lipids (such as lipin-1 generated diacylglycerol) within foam cells leads to the inadvertent activation of signaling cascades that result in macrophage pro-inflammatory cytokine responses. Furthermore, the observation that lipin-1 seems to more significantly contribute to oxLDL-elicited pro-inflammatory responses than that observed for LPS stimulation 16 suggests that targeting lipin-1 enzymatic activity may reduce atherosclerotic inflammation without rendering individuals susceptible to bacterial infection. Whether the modulation of lipin-1 activity can provide therapeutic benefits for the treatment of atherosclerosis and CVD will be the focus of future research.…”

Section: Resultsmentioning

confidence: 96%

“…Macrophages require lipin-1 for PGE 2 and pro-inflammatory cytokine production in response to LPS and the intracellular bacteria Francisella tularensis 15–16 . We demonstrate here that short-term oxLDL treatment (24 hours) fails to elicit pro-inflammatory cytokine responses, in agreement with work by Spann et.al, who demonstrated that cholesterol uptake by macrophages results in an anti-inflammatory macrophage phenotype 33 .…”

Section: Discussionmentioning

confidence: 99%

“…In human and mouse macrophages, lipin-1 contributes to lipid droplet formation following fatty acid loading 14 . Additionally, we and others have demonstrated that lipin-1 regulates macrophage inflammatory activity in response to both the intracellular pathogen Francisella tularensis 15 and to lipopolysaccharide (LPS) 16 . These studies demonstrate that lipin-1 is involved in two cellular events that are known to exist in macrophage foam cells; storage of engulfed cholesterol/lipids and pro-inflammatory activity, suggesting to us that lipin-1 may link lipid synthesis pathways that contribute to foam cell formation to foam cell inflammatory mediator production.…”

Section: Introductionmentioning

confidence: 97%

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Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

et al. 2015

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Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries and the underlying cause of cardiovascular disease, a major cause of mortality worldwide. The over-accumulation of modified cholesterol-containing low-density lipoproteins (e.g. oxLDL) in the artery wall and the subsequent recruitment and activation of macrophages contributes to the development of atherosclerosis. The excessive uptake of modified-LDL by macrophages leads to a lipid-laden “foamy” phenotype and pro-inflammatory cytokine production. Modified-LDLs promote foam cell formation in part by stimulating de novo lipid biosynthesis. However, it is unknown if lipid biosynthesis directly regulates foam cell pro-inflammatory mediator production. Lipin-1, a phosphatidate phosphohydrolase required for the generation of diacylglycerol during glycerolipid synthesis has recently been demonstrated to contribute to bacterial-induced pro-inflammatory responses by macrophages. In this study we present evidence demonstrating the presence of lipin-1 within macrophages in human atherosclerotic plaques. Additionally, reducing lipin-1 levels in macrophages significantly inhibits both modified-LDL-induced foam cell formation in vitro, as observed by smaller/fewer intracellular lipid inclusions, and ablates modified-LDL-elicited production of the pro-atherogenic mediators tumor necrosis factor-α, interleukin-6, and prostaglandin E2. These findings demonstrate a critical role for lipin-1 in the regulation of macrophage inflammatory responses to modified-LDL. These data begin to link the processes of foam cell formation and pro-inflammatory cytokine production within macrophages.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

et al. 2015

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“…Adherent macrophages were then used for experimentation. When mice were treated with LPS, the animals were intraperitoneally injected with LPS at a dose of 5 mg/kg for 6 hr, after which the animals were euthanized with ketamine (100 mg/kg)/xylacine (10 mg/kg) and cervical dislocation (Meana et al, 2014). All the protocols and procedures were approved by the Institutional Animal Care and Usage Committee of the University of Valladolid, and are in accordance with the Spanish and European Union guidelines for the use of experimental animals.…”

Section: Experimental Procedures Cell Isolation and Culture Conditionsmentioning

confidence: 99%

Foamy Monocytes Are Enriched in cis -7-Hexadecenoic Fatty Acid (16:1n-9), a Possible Biomarker for Early Detection of Cardiovascular Disease

Guijas

Meana

Astudillo

et al. 2016

Cell Chemical Biology

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Human monocytes respond to arachidonic acid, a secretory product of endothelial cells, by activating the de novo pathway of fatty acid biosynthesis, resulting in the acquisition of a foamy phenotype due to accumulation of cytoplasmic lipid droplets. Recruitment of foamy monocytes to endothelium is a key step in the formation of atherosclerotic plaques. Here we describe that lipid droplets of foamy monocytes are enriched in a rather uncommon fatty acid, cis-7-hexadecenoic acid (16:1n-9), a positional isomer of palmitoleic acid. 16:1n-9 was found to possess an anti-inflammatory activity both in vitro and in vivo that is comparable with that of omega-3 fatty acids and clearly distinguishable from the effects of palmitoleic acid. Selective accumulation in neutral lipids of phagocytic cells of an uncommon fatty acid reveals an early phenotypic change that may provide a biomarker of proatherogenicity, and a potential target for intervention in the early stages of cardiovascular disease.

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“…Lipopolysaccharide (LPS) and pro-inflammatory cytokines such as TNF-α, IL-1β, and IFN-γ decrease lipin-1 mRNA and protein, but not lipin-2 or lipin-3,in mouse adipose tissue and in cultured 3T3-L1 adipocytes (60–62). Paradoxically, a recent study has revealed an unexpected role for lipin-1 as a mediator of macrophage proinflammatory activation (63). Upon Toll- Like-Receptor (TLR4) stimulation of macrophages from lipin-1-deficient animals and human macrophages deficient in the lipin-1 enzyme, the generation of proinflammatory cytokines known to be involved in inflammatory process, was reduced, suggesting that lipin-1-PAP acts as a proinflammatory mediator downstream of TLR signaling and during the development of inflammatory processes in macrophage (63).…”

Section: Role Of Lipin-1 In Afldmentioning

confidence: 99%

Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1

You¹,

Jogasuria²,

Lee³

et al. 2017

CMP

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Lipin-1, a mammalian phosphatidic acid phosphatase (PAP), is a bi-functional molecule involved in various signaling pathways via its function as a PAP enzyme in the triglyceride synthesis pathway and in the nucleus as a transcriptional co-regulator. In the liver, lipin-1 is known to play a vital role in controlling the lipid metabolism and inflammation process at multiple regulatory levels. Alcoholic fatty liver disease (AFLD) is one of the earliest forms of liver injury and approximately 8–20% of patients with simple steatosis can develop into more severe forms of liver injury, including steatohepatitis, fibrosis/cirrhosis, and eventually hepatocellular carcinoma (HCC). The signal transduction mechanisms for alcohol-induced detrimental effects in liver involves alteration of complex and multiple signaling pathways largely governed by a central and upstream signaling system, namely, sirtuin 1 (SIRT1)-AMP activated kinase (AMPK) axis. Emerging evidence suggests a pivotal role of lipin-1 as a crucial downstream regulator of SIRT1-AMPK signaling system that is likely to be ultimately responsible for development and progression of AFLD. Several lines of evidence demonstrate that ethanol exposure significantly induces lipin-1 gene and protein expression levels in cultured hepatocytes and in the livers of rodents, induces lipin-1-PAP activity, impairs the functional activity of nuclear lipin-1, disrupts lipin-1 mRNA alternative splicing and induces lipin-1 nucleocytoplasmic shuttling. Such impairment in response to ethanol leads to derangement of hepatic lipid metabolism, and excessive production of inflammatory cytokines in the livers of the rodents and human alcoholics. This review summarizes current knowledge about the role of lipin-1 in the pathogenesis of AFLD and its potential signal transduction mechanisms.

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Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

Cited by 47 publications

References 42 publications

Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

Foamy Monocytes Are Enriched in cis -7-Hexadecenoic Fatty Acid (16:1n-9), a Possible Biomarker for Early Detection of Cardiovascular Disease

Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1

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