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1.
Curr Opin Lipidol ; 33(3): 193-198, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35165232

RESUMEN

PURPOSE OF REVIEW: The turnover of fatty acids (FAs) at the sn-2 position of phospholipids is mediated by the reciprocal actions of phospholipases A2 and lyso-PL acyltransferases (LPLAT). LPCAT3, a major LPLAT isoform, exhibits a strong specificity for polyunsaturated FAs s (PUFAs). Although the enzyme was originally studied in the context of cardiometabolism, recent investigations have shed light on the role of LPCAT3 in other tissues such as skeletal muscle and in unexpected biological processes such as cell death and oncogenesis. RECENT FINDINGS: The three-dimensional structure of LPCAT3 has been elucidated allowing further understanding of the mechanism of the acylation reaction as well as the substrate specificity of the enzyme. In skeletal muscle, LPCAT3-mediated phospholipid remodeling modulates membrane domain clustering and insulin signalingLPCAT3 plays an important role in the process of ferroptosis by modulating the PUFA content of phospholipids and possibly of plasmalogens.In tumor-associated macrophages, LPCAT3 can prevent ER stress induced by the tumor microenvironment and may equally modulate antitumor immunity. SUMMARY: LPCAT3 is an attractive therapeutic target in the cardiometabolic disorders. Nevertheless, the involvement of LPCAT3 in processes such as cell death and oncogenesis demands caution with respect to the potential deleterious effects of enzyme modulation.


Asunto(s)
1-Acilglicerofosfocolina O-Aciltransferasa , Fosfolípidos , 1-Acilglicerofosfocolina O-Aciltransferasa/genética , Aciltransferasas , Carcinogénesis , Humanos , Fosfatidilcolina-Esterol O-Aciltransferasa , Fosfatidilcolinas/metabolismo , Fosfolípidos/metabolismo , Microambiente Tumoral
2.
Am J Transplant ; 22(5): 1350-1361, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35038785

RESUMEN

Acute graft-versus-host disease (aGVHD) is a major limitation of the therapeutic potential of allogeneic hematopoietic cell transplantation. Lipopolysaccharides (LPS) derived from intestinal gram-negative bacteria are well-known aGVHD triggers and amplifiers. Here, we explored the LPS metabolism in aGVHD mouse models using an innovative quantification method. We demonstrated that systemic LPS accumulation after transplantation was due, at least partly, to a defect in its clearance through lipoprotein-mediated transport to the liver (i.e., the so-called reverse LPS transport). After transplantation, reduced circulating HDL concentration impaired LPS neutralization and elimination through biliary flux. Accordingly, HDL-deficient (Apoa1tm1Unc ) recipient mice developed exacerbated aGVHD. Repeated administration of HDL isolated from human plasma significantly decreased the mortality and the severity of aGVHD. While the potential role of HDL in scavenging circulating LPS was examined in this study, it appears that HDL plays a more direct immunomodulatory role by limiting or controlling aGVHD. Notably, HDL infusion mitigated liver aGVHD by diminishing immune infiltration (e.g., interferon-γ-secreting CD8+ T cells and non-resident macrophages), systemic and local inflammation (notably cholangitis). Hence, our results revealed the interest of HDL-based therapies in the prevention of aGVHD.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Aguda , Animales , Linfocitos T CD8-positivos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Lipopolisacáridos/metabolismo , Lipoproteínas HDL/metabolismo , Ratones , Trasplante Homólogo
3.
Int J Obes (Lond) ; 46(10): 1892-1900, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35933445

RESUMEN

AIMS/HYPOTHESIS: Translocation of bacterial debris from the gut causes metabolic endotoxemia (ME) that results in insulin resistance, and may be on the causal pathway to obesity-related type 2 diabetes. To guide interventions against ME we tested two hypothesised mechanisms for lipopolysaccharide (LPS) ingress: a leaky gut and chylomicron-associated transfer following a high-fat meal. METHODS: In lean women (n = 48; fat mass index (FMI) 9.6 kg/m2), women with obesity (n = 62; FMI 23.6 kg/m2) and women with obesity-diabetes (n = 38; FMI 24.9 kg/m2) we used the lactulose-mannitol dual-sugar permeability test (LM ratio) to assess gut integrity. Markers of ME (LPS, EndoCAb IgG and IgM, IL-6, CD14 and lipoprotein binding protein) were assessed at baseline, 2 h and 5 h after a standardised 49 g fat-containing mixed meal. mRNA expression of markers of inflammation, macrophage activation and lipid metabolism were measured in peri-umbilical adipose tissue (AT) biopsies. RESULTS: The LM ratio did not differ between groups. LPS levels were 57% higher in the obesity-diabetes group (P < 0.001), but, contrary to the chylomicron transfer hypothesis, levels significantly declined following the high-fat challenge. EndoCAb IgM was markedly lower in women with obesity and women with obesity-diabetes. mRNA levels of inflammatory markers in adipose tissue were consistent with the prior concept that fat soluble LPS in AT attracts and activates macrophages. CONCLUSIONS/INTERPRETATION: Raised levels of LPS and IL-6 in women with obesity-diabetes and evidence of macrophage activation in adipose tissue support the concept of metabolic endotoxemia-mediated inflammation, but we found no evidence for abnormal gut permeability or chylomicron-associated post-prandial translocation of LPS. Instead, the markedly lower EndoCAb IgM levels indicate a failure in sequestration and detoxification.


Asunto(s)
Diabetes Mellitus Tipo 2 , Endotoxemia , Quilomicrones , Diabetes Mellitus Tipo 2/complicaciones , Endotoxemia/etiología , Femenino , Gambia , Humanos , Inmunoglobulina G , Inmunoglobulina M , Inflamación/metabolismo , Interleucina-6 , Lactulosa , Lipopolisacáridos/metabolismo , Lipoproteínas/metabolismo , Manitol , Obesidad/metabolismo , ARN Mensajero
4.
Cardiovasc Diabetol ; 21(1): 272, 2022 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-36471375

RESUMEN

Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of lipoproteins. ApoC1 is involved in the metabolism of triglyceride-rich lipoproteins by inhibiting the binding of very low density lipoproteins (VLDL) to VLDL-receptor (VLDL-R), to low density lipoprotein receptor (LDL-R) and to LDL receptor related protein (LRP), by reducing the activity of lipoprotein lipase (LPL) and by stimulating VLDL production, all these effects leading to increase plasma triglycerides. ApoC1 takes also part in the metabolism of high density lipoproteins (HDL) by inhibiting Cholesterol Ester Transfer Protein (CETP). The functionality of apoC1 on CETP activity is impaired in diabetes that might account, at least in part, for the increased plasma CETP activity observed in patients with diabetes. Its different effects on lipoprotein metabolism with a possible role in the modulation of inflammation makes the net impact of apoC1 on cardiometabolic risk difficult to figure out and apoC1 might be considered as pro-atherogenic or anti-atherogenic depending on the overall metabolic context. Making the link between total plasma apoC1 levels and the risk of cardio-metabolic diseases is difficult due to the high exchangeability of this small protein whose biological effects might depend essentially on its association with VLDL or HDL. The role of apoC1 in humans is not entirely elucidated and further studies are needed to determine its precise role in lipid metabolism and its possible pleiotropic effects on inflammation and vascular wall biology. In this review, we will present data on apoC1 structure and distribution among lipoproteins, on the effects of apoC1 on VLDL metabolism and HDL metabolism and we will discuss the possible links between apoC1, atherosclerosis and diabetes.


Asunto(s)
Apolipoproteína C-I , Aterosclerosis , Diabetes Mellitus , Lipoproteínas HDL , Lipoproteínas VLDL , Humanos , Apolipoproteína C-I/metabolismo , Aterosclerosis/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Diabetes Mellitus/metabolismo , Inflamación/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas VLDL/metabolismo , Triglicéridos
5.
Int J Mol Sci ; 23(21)2022 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-36362012

RESUMEN

Bacterial lipopolysaccharides (LPS, endotoxins) are found in high amounts in the gut lumen. LPS can cross the gut barrier and pass into the blood (endotoxemia), leading to low-grade inflammation, a common scheme in metabolic diseases. Phospholipid transfer protein (PLTP) can transfer circulating LPS to plasma lipoproteins, thereby promoting its detoxification. However, the impact of PLTP on the metabolic fate and biological effects of gut-derived LPS is unknown. This study aimed to investigate the influence of PLTP on low-grade inflammation, obesity and insulin resistance in relationship with LPS intestinal translocation and metabolic endotoxemia. Wild-type (WT) mice were compared with Pltp-deficient mice (Pltp-KO) after a 4-month high-fat (HF) diet or oral administration of labeled LPS. On a HF diet, Pltp-KO mice showed increased weight gain, adiposity, insulin resistance, lipid abnormalities and inflammation, together with a higher exposure to endotoxemia compared to WT mice. After oral administration of LPS, PLTP deficiency led to increased intestinal translocation and decreased association of LPS to lipoproteins, together with an altered catabolism of triglyceride-rich lipoproteins (TRL). Our results show that PLTP, by modulating the intestinal translocation of LPS and plasma processing of TRL-bound LPS, has a major impact on low-grade inflammation and the onset of diet-induced metabolic disorders.


Asunto(s)
Dieta Alta en Grasa , Endotoxemia , Inflamación , Resistencia a la Insulina , Aumento de Peso , Animales , Ratones , Dieta Alta en Grasa/efectos adversos , Endotoxemia/inducido químicamente , Endotoxemia/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Lipopolisacáridos/efectos adversos , Lipoproteínas/metabolismo , Obesidad/etiología , Proteínas de Transferencia de Fosfolípidos/genética , Proteínas de Transferencia de Fosfolípidos/metabolismo , Aumento de Peso/fisiología
6.
J Lipid Res ; 62: 100011, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33500240

RESUMEN

Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS transfer assays to assess the ability of CETP to bind and transfer LPS. The effects of intravenous (iv) infusion of purified LPS or polymicrobial infection (cecal ligation and puncture [CLP]) were compared in transgenic mice expressing human CETP and wild-type mice naturally having no CETP activity. CETP displayed no LPS transfer activity in vitro, but it tended to reduce biliary excretion of LPS in vivo. The CETP expression in mice was associated with significantly lower basal plasma lipid levels and with higher mortality rates in both models of endotoxemia and sepsis. Furthermore, CETPTg plasma modified cytokine production of macrophages in vitro. In conclusion, despite having no direct LPS binding and transfer property, human CETP worsens sepsis outcomes in mice by altering the protective effects of plasma lipoproteins against endotoxemia, inflammation, and infection.


Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol
7.
J Lipid Res ; 62: 100013, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33518513

RESUMEN

Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these organs, LPCAT3 critically supports cell-membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3's role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approximately 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid [AA]) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr-/-) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.


Asunto(s)
1-Acilglicerofosfocolina O-Aciltransferasa
8.
J Lipid Res ; 61(12): 1776-1783, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33037132

RESUMEN

Lipopolysaccharide (LPS) is a key player for innate immunity activation. It is therefore a prime target for sepsis treatment, as antibiotics are not sufficient to improve outcome during septic shock. An extracorporeal removal method by polymyxin (PMX) B direct hemoperfusion (PMX-DHP) is used in Japan, but recent trials failed to show a significant lowering of circulating LPS levels after PMX-DHP therapy. PMX-DHP has a direct effect on LPS molecules. However, LPS is not present in a free form in the circulation, as it is mainly carried by lipoproteins, including LDLs. Lipoproteins are critical for physiological LPS clearance, as LPSs are carried by LDLs to the liver for elimination. We hypothesized that LDL apheresis could be an alternate method for LPS removal. First, we demonstrated in vitro that LDL apheresis microbeads are almost as efficient as PMX beads to reduce LPS concentration in LPS-spiked human plasma, whereas it is not active in PBS. We found that PMX was also adsorbing lipoproteins, although less specifically. Then, we found that endogenous LPS of patients treated by LDL apheresis for familial hypercholesterolemia is also removed during their LDL apheresis sessions, with both electrostatic-based devices and filtration devices. Finally, LPS circulating in the plasma of septic shock and severe sepsis patients with gram-negative bacteremia was also removed in vitro by LDL adsorption. Overall, these results underline the importance of lipoproteins for LPS clearance, making them a prime target to study and treat endotoxemia-related conditions.


Asunto(s)
Hemoperfusión , Lipopolisacáridos/sangre , Lipopolisacáridos/aislamiento & purificación , Sepsis/sangre , Sepsis/terapia , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino
9.
Liver Int ; 39(1): 106-114, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29931819

RESUMEN

BACKGROUND & AIMS: The quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3-hydroxymyristate (3-HM), a lipid component of LPS, and to evaluate correlations between 3-HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage. METHODS: Plasma from 90 noninfected cirrhotic patients (30 Child-Pugh [CP]-A, 30 CP-B, 30 CP-C) was prospectively collected. The concentration of 3-HM was determined by high-performance liquid chromatography coupled with mass spectrometry. RESULTS: 3-HM levels were higher in CP-C patients (CP-A/CP-B/CP-C: 68/70/103 ng/mL, P = 0.005). Patients with severe acute alcoholic hepatitis (n = 16; 113 vs 74 ng/mL, P = 0.012), diabetic patients (n = 22; 99 vs 70 ng/mL, P = 0.028) and those not receiving beta blockers (n = 44; 98 vs 72 ng/mL, P = 0.034) had higher levels of 3-HM. We observed a trend towards higher baseline levels of 3-HM in patients with hepatic encephalopathy (n = 7; 144 vs 76 ng/mL, P = 0.45) or SIRS (n = 10; 106 vs 75 ng/mL, P = 0.114). In multivariate analysis, high levels of 3-HM were associated with CP (OR = 4.39; 95%CI = 1.79-10.76) or MELD (OR = 8.24; 95%CI = 3.19-21.32) scores. Patients dying from liver insufficiency (n = 6) during a 12-month follow-up had higher baseline levels of 3-HM (106 vs 75 ng/mL, P = 0.089). CONCLUSIONS: In noninfected cirrhotic patients, 3-HM arises more frequently with impairment of liver function, heavy alcohol consumption, diabetic status, nonuse of beta blockers and a trend towards poorer outcome is also observed. The direct mass measurement of LPS using 3-HM appears reliable to detect transient endotoxaemia and promising to manage the follow-up of cirrhotic patients.


Asunto(s)
Análisis Químico de la Sangre/métodos , Endotoxemia/diagnóstico , Lipopolisacáridos/sangre , Cirrosis Hepática/sangre , Ácidos Mirísticos/sangre , Anciano , Biomarcadores/sangre , Cromatografía Líquida de Alta Presión , Femenino , Encefalopatía Hepática/sangre , Encefalopatía Hepática/complicaciones , Humanos , Cirrosis Hepática/diagnóstico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Proyectos Piloto , Factores de Riesgo , Índice de Severidad de la Enfermedad
10.
Int J Mol Sci ; 20(15)2019 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-31382500

RESUMEN

Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has constituted a limitation to the clinical development of pharmacological LXR agonists. However, recent studies provided a different perspective. Beyond the quantitative accumulation of FA, it appears that LXRs induce qualitative changes in the FA profile and in the distribution of FAs among cellular lipid species. Thus, LXRs activate the production of polyunsaturated fatty acids (PUFAs) and their distribution into phospholipids via the control of FA desaturases, FA elongases, lysophosphatidylcholine acyltransferase (LPCAT3), and phospholipid transfer protein (PLTP). Therefore, LXRs control, in a dynamic manner, the PUFA composition and the physicochemical properties of cell membranes as well as the release of PUFA-derived lipid mediators. Recent studies suggest that modulation of PUFA and phospholipid metabolism by LXRs are involved in the control of lipogenesis and lipoprotein secretion by the liver. In myeloid cells, the interplay between LXR and PUFA metabolism affects the inflammatory response. Revisiting the complex role of LXRs in FA metabolism may open new opportunities for the development of LXR modulators in the field of cardiometabolic diseases.


Asunto(s)
Ácidos Grasos Insaturados/metabolismo , Receptores X del Hígado/metabolismo , Hígado/metabolismo , Fosfolípidos/metabolismo , Animales , Homeostasis , Humanos , Inflamación/metabolismo , Lipogénesis , Lipoproteínas VLDL/metabolismo
11.
Blood ; 128(23): 2694-2707, 2016 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-27702801

RESUMEN

Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach.


Asunto(s)
Antineoplásicos/farmacología , Colesterol/metabolismo , Células Dendríticas/metabolismo , Receptores X del Hígado/agonistas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Dendríticas/patología , Femenino , Humanos , Interleucina-3/metabolismo , Receptores X del Hígado/metabolismo , Masculino , Ratones , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT5/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Curr Opin Lipidol ; 28(1): 19-26, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27870652

RESUMEN

PURPOSE OF REVIEW: Recent studies have highlighted that macrophages dynamically and autonomously handle all the facets of fatty acid (FA) metabolism including FA oxidation and FA synthesis as well as the synthesis of monounsaturated FAs and long chain n-3 and n-6 polyunsaturated FAs. RECENT FINDINGS: Macrophage M2 polarization is associated with an increase of FA oxidation. However, whether increased FA oxidation simply correlates with or is required for M2 polarization needs to be further evaluated. Macrophage M1 polarization is associated with the activation of FA synthesis, which directly contributes to the inflammatory response and affects cholesterol homeostasis and neutral lipid accumulation. Finally, recent evidences suggest that macrophages are able to autonomously produce signaling monounsaturated FAs, such as palmitoleic acid (C16 : 1 n-7), and long chain n-3 and n-6 polyunsaturated FAs, such as arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. This pathway is regulated by liver X receptors and has significant consequences on inflammation and on the FA composition of atheroma plaques. SUMMARY: These studies shed new light on the tight relationship between FA metabolism, macrophage polarization, and M1/M2 macrophage functions. These processes may have major consequences for atherosclerosis pathogenesis as well as other metabolic disorders.


Asunto(s)
Ácidos Grasos/metabolismo , Macrófagos/metabolismo , Enfermedades Metabólicas/inmunología , Enfermedades Metabólicas/metabolismo , Animales , Ácidos Grasos/biosíntesis , Humanos , Oxidación-Reducción
13.
J Lipid Res ; 58(10): 1950-1961, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28765208

RESUMEN

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apoB-containing lipoproteins, i.e., the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo. We showed that, in mice with a genetically engineered deficiency for the plasma lipid transporter, phospholipid transfer protein (PLTP), abnormally low circulating cholesterol concentrations were associated with a significant prolongation of survival time after intraperitoneal inoculation of the 22L prion strain. Moreover, when circulating cholesterol levels rose after feeding PLTP-deficient mice a lipid-enriched diet, a significant reduction in survival time of mice together with a marked increase in the accumulation rate of PrPSc deposits in their brain were observed. Our results suggest that the circulating cholesterol level is a determinant of prion propagation in vivo and that cholesterol-lowering strategies might be a successful therapeutic approach for patients suffering from prion diseases.


Asunto(s)
Colesterol/sangre , Priones/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Técnicas de Inactivación de Genes , Ratones , Ratones Endogámicos C57BL , Proteínas de Transferencia de Fosfolípidos/deficiencia , Proteínas de Transferencia de Fosfolípidos/genética , Análisis de Supervivencia
14.
Hum Mol Genet ; 24(23): 6603-13, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26358774

RESUMEN

Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective glycosylation secondary to mutations in the VPS13B gene, which encodes a protein of the Golgi apparatus. Besides congenital neutropenia, retinopathy and intellectual deficiency, CS patients are faced with truncal obesity. Metabolism investigations showed abnormal glucose tolerance tests and low HDL values in some patients, and these could be risk factors for the development of diabetes mellitus and/or cardiovascular complications. To understand the mechanisms involved in CS fat storage, we used two models of adipogenesis differentiation: (i) SGBS pre-adipocytes with VPS13B invalidation thanks to siRNA delivery and (ii) CS primary fibroblasts. In both models, VPS13B invalidation led to accelerated differentiation into fat cells, which was confirmed by the earlier and increased expression of specific adipogenic genes, consequent to the increased response of cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 phosphorylation after insulin stimulation, which suggests insulin resistance. This study, in association with the in-depth analysis of the metabolic status of the patients, thus allowed us to recommend appropriate nutritional education to prevent the occurrence of diabetes mellitus and to put forward recommendations for the follow-up of CS patients, in particular with regard to the development of metabolic syndrome. We also suggest replacing the term obesity by abnormal fat distribution in CS, which should reduce the number of inappropriate diagnoses in patients who are referred only on the basis of intellectual deficiency associated with obesity.


Asunto(s)
Adipogénesis , Distribución de la Grasa Corporal , Diabetes Mellitus Tipo 2/fisiopatología , Dedos/anomalías , Insulina/fisiología , Discapacidad Intelectual/fisiopatología , Microcefalia/fisiopatología , Hipotonía Muscular/fisiopatología , Miopía/fisiopatología , Obesidad/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/fisiopatología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etiología , Femenino , Dedos/fisiopatología , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Microcefalia/complicaciones , Persona de Mediana Edad , Modelos Biológicos , Hipotonía Muscular/complicaciones , Mutación , Miopía/complicaciones , Obesidad/complicaciones , Degeneración Retiniana , Riesgo , Transducción de Señal , Proteínas de Transporte Vesicular/genética , Adulto Joven
15.
Arterioscler Thromb Vasc Biol ; 35(6): 1357-65, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25838428

RESUMEN

OBJECTIVE: Liver X receptors (LXRs) modulate cholesterol and fatty acid homeostasis as well as inflammation. This study aims to decipher the role of LXRs in the regulation of polyunsaturated fatty acid (PUFA) synthesis in macrophages in the context of atherosclerosis. APPROACH AND RESULTS: Transcriptomic analysis in human monocytes and macrophages was used to identify putative LXR target genes among enzymes involved in PUFA biosynthesis. In parallel, the consequences of LXR activation or LXR invalidation on PUFA synthesis and distribution were determined. Finally, we investigated the impact of LXR activation on PUFA metabolism in vivo in apolipoprotein E-deficient mice. mRNA levels of acyl-CoA synthase long-chain family member 3, fatty acid desaturases 1 and 2, and fatty acid elongase 5 were significantly increased in human macrophages after LXR agonist treatment, involving both direct and sterol responsive element binding protein-1-dependent mechanisms. Subsequently, pharmacological LXR agonist increased long chain PUFA synthesis and enhanced arachidonic acid content in the phospholipids of human macrophages. Increased fatty acid desaturases 1 and 2 and acyl-CoA synthase long-chain family member 3 mRNA levels as well as increased arachidonic acid to linoleic acid and docosahexaenoic acid to eicosapentaenoic acid ratios were also found in atheroma plaque and peritoneal foam cells from LXR agonist-treated mice. By contrast, murine LXR-deficient macrophages displayed reduced expression of fatty acid elongase 5, acyl-CoA synthase long-chain family member 3 and fatty acid desaturases 1, as well as decreased cellular levels of docosahexaenoic acid and arachidonic acid. CONCLUSIONS: Our results indicate that LXR activation triggers PUFA synthesis in macrophages, which results in significant alterations in the macrophage lipid composition. Moreover, we demonstrate here that LXR agonist treatment modulates PUFA metabolism in atherosclerotic arteries.


Asunto(s)
Aterosclerosis/metabolismo , Ácidos Grasos Insaturados/biosíntesis , Macrófagos/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Animales , Ácido Araquidónico/metabolismo , Arterias/metabolismo , Células Espumosas/metabolismo , Humanos , Receptores X del Hígado , Ratones , Receptores Nucleares Huérfanos/agonistas , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo
16.
J Lipid Res ; 56(7): 1363-9, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26023073

RESUMEN

Quantitation of plasma lipopolysaccharides (LPSs) might be used to document Gram-negative bacterial infection. In the present work, LPS-derived 3-hydroxymyristate was extracted from plasma samples with an organic solvent, separated by reversed phase HPLC, and quantitated by MS/MS. This mass assay was combined with the limulus amebocyte lysate (LAL) bioassay to monitor neutralization of LPS activity in biological samples. The described HPLC/MS/MS method is a reliable, practical, accurate, and sensitive tool to quantitate LPS. The combination of the LAL and HPLC/MS/MS analyses provided new evidence for the intrinsic capacity of plasma lipoproteins and phospholipid transfer protein to neutralize the activity of LPS. In a subset of patients with systemic inflammatory response syndrome, with documented infection but with a negative plasma LAL test, significant amounts of LPS were measured by the HPLC/MS/MS method. Patients with the highest plasma LPS concentration were more severely ill. HPLC/MS/MS is a relevant method to quantitate endotoxin in a sample, to assess the efficacy of LPS neutralization, and to evaluate the proinflammatory potential of LPS in vivo.


Asunto(s)
Análisis Químico de la Sangre/métodos , Cangrejos Herradura , Lipopolisacáridos/sangre , Proteínas de la Membrana/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Lipopolisacáridos/química , Lipopolisacáridos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Espectrometría de Masas en Tándem
17.
Crit Care Med ; 42(5): 1065-73, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24413578

RESUMEN

OBJECTIVES: Systemic inflammatory response syndrome and sepsis frequently occur after cardiac surgery with cardiopulmonary bypass. The aim of the present study was to investigate whether preoperative cholesterol levels can predict sepsis onset and postoperative complications in patients undergoing cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective observational study. SETTING: Surgical ICU of a French university hospital. PATIENTS: Two hundred and seventeen consecutive patients older than 18 years admitted for planned cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Measurements of plasma blood lipids and inflammation markers before anesthesia induction (baseline), at cardiopulmonary bypass start, at cardiopulmonary bypass end, and 3 and 24 hours after cardiac surgery. Outcomes were compared in systemic inflammatory response syndrome patients with sepsis (n = 15), systemic inflammatory response syndrome patients without sepsis (n = 95), and non-systemic inflammatory response syndrome patients (n = 107). MEASUREMENTS AND MAIN RESULTS: A gradual decrease in plasma cholesterol concentration occurred during surgery with cardiopulmonary bypass but was no longer present after correction for hemodilution. Corrected cholesterol levels were significantly lower at baseline in sepsis patients than in other subgroups, and it remained lower in the sepsis group during and after cardiopulmonary bypass. With regard to sepsis, the discriminatory power of baseline cholesterol was fairly good as indicated by receiver operating characteristic curve analysis (area under the curve, 0.78; 95% CI, 0.72-0.84). The frequency of sepsis progressively decreased with increasing baseline cholesterol level quintiles (18.6% and 0% in the bottom and top quintiles, respectively, p = 0.005). In multivariate analysis, baseline cholesterol levels and cardiopulmonary bypass duration were significant and independent determinants of the 3-hour postcardiopulmonary bypass increase in concentrations of procalcitonin and interleukin-8, but not of interleukin-6. CONCLUSIONS: Low cholesterol levels before elective cardiac surgery with cardiopulmonary bypass may be a simple biomarker for the early identification of patients with a high risk of sepsis.


Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Puente Cardiopulmonar/efectos adversos , Colesterol/sangre , Complicaciones Posoperatorias/etiología , Sepsis/etiología , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Anciano , Área Bajo la Curva , Biomarcadores/análisis , Calcitonina/análisis , Péptido Relacionado con Gen de Calcitonina , Cuidados Críticos , Citocinas/análisis , Procedimientos Quirúrgicos Electivos , Femenino , Humanos , Lipoproteínas/análisis , Modelos Logísticos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico , Estudios Prospectivos , Precursores de Proteínas/análisis , Factores de Riesgo , Sepsis/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Resultado del Tratamiento
18.
Am J Pathol ; 183(3): 975-86, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23830874

RESUMEN

Plasma phospholipid transfer protein (PLTP) increases the circulating levels of proatherogenic lipoproteins, accelerates blood coagulation, and modulates inflammation. The role of PLTP in the development of abdominal aortic aneurysm (AAA) was investigated by using either a combination of mechanical and elastase injury at one site of mouse aorta (elastase model) or continuous infusion of angiotensin II in hyperlipidemic ApoE-knockout mice (Ang II model). With the elastase model, complete PLTP deficiency was associated with a significantly lower incidence and a lesser degree of AAA expansion. With the Ang II model, findings were consistent with those in the elastase model, with a lower severity grade in PLTP-deficient mice, an intermediate phenotype in PLTP-deficient heterozygotes, and a blunted effect of the PLTP-deficient trait when restricted to bone marrow-derived immune cells. The protective effect of whole-body PLTP deficiency in AAA was illustrated further by a lesser degree of adventitia expansion, reduced elastin degradation, fewer recruited macrophages, and less smooth muscle cell depletion in PLTP-deficient than in wild-type mice, as evident from comparative microscopic analysis of aorta sections. Finally, cumulative evidence supports the association of PLTP deficiency with reduced expression and activity levels of matrix metalloproteinases, known to degrade elastin and collagen. We conclude that PLTP can play a significant role in the pathophysiology of AAA.


Asunto(s)
Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Proteínas de Transferencia de Fosfolípidos/deficiencia , Proteínas de Transferencia de Fosfolípidos/metabolismo , Angiotensina II , Animales , Aorta/patología , Aneurisma de la Aorta Abdominal/complicaciones , Apolipoproteínas E/deficiencia , Linfocitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Elastina/metabolismo , Inflamación/complicaciones , Inflamación/patología , Hígado/metabolismo , Hígado/patología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Elastasa Pancreática
19.
Arterioscler Thromb Vasc Biol ; 33(6): 1171-9, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23580142

RESUMEN

OBJECTIVE: Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that are highly expressed in macrophages and regulate lipid homeostasis and inflammation. Among putative LXR target genes, lysophosphatidylcholine acyltransferase 3 (LPCAT3) involved in the Lands cycle controls the fatty acid composition at the sn-2 position of glycerophospholipids and, therefore, the availability of fatty acids, such as arachidonic acid (AA), used for eicosanoid synthesis. The aim of our study was to determine whether LXRs could regulate the Lands cycle in human macrophages, to assess the consequences in terms of lipid composition and inflammatory response, and to work out the relative contribution of LPCAT3 to the observed changes. APPROACH AND RESULTS: Transcriptomic analysis revealed that LPCAT3 was upregulated by LXR agonists in human macrophages. Accordingly, LXR stimulation significantly increased lysophospholipid acyltransferase activity catalyzed by LPCAT3. Lipidomic analysis demonstrated that LXR activation increased the AA content in the polar lipid fraction, specifically in phosphatidylcholines. The LXR-mediated effects on AA distribution were abolished by LPCAT3 silencing, and a redistribution of AA toward the neutral lipid fraction was observed in this context. Finally, we observed that preconditioning of human macrophages by LXR agonist treatment increased the release of arachidonate-derived eicosanoids, such as prostaglandin E2 and thromboxane after lipopolysaccharide stimulation, with a significant attenuation by LPCAT3 silencing. CONCLUSIONS: Altogether, our data demonstrate that the LXR-mediated induction of LPCAT3 primes human macrophages for subsequent eicosanoid secretion by increasing the pool of AA, which can be mobilized from phospholipids.


Asunto(s)
1-Acilglicerofosfocolina O-Aciltransferasa/genética , Ácido Araquidónico/metabolismo , Eicosanoides/metabolismo , Inflamación/genética , Macrófagos/metabolismo , Receptores Nucleares Huérfanos/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferasa/metabolismo , Células Cultivadas , Dimetilsulfóxido/farmacología , Dinoprostona/metabolismo , Humanos , Inflamación/fisiopatología , Receptores X del Hígado , Macrófagos/efectos de los fármacos , Análisis por Micromatrices , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Receptores Nucleares Huérfanos/efectos de los fármacos , ARN Mensajero/análisis , Sensibilidad y Especificidad , Regulación hacia Arriba/genética
20.
J Crit Care ; 79: 154438, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37797404

RESUMEN

PURPOSE: Gut can be a source of sepsis but sepsis itself can induce gut dysfunction. We aimed to study whether plasma citrulline, a marker of enterocyte mass, was correlated with plasma lipopolysaccharide, a potential marker of bacterial translocation among critically ill patients. MATERIALS AND METHODS: Critically ill patients admitted to the ICU. Plasma citrulline and plasma LPS concentration and activity were measured at ICU admission. Patients were compared according to the presence of sepsis at ICU admission. RESULTS: 109 critically ill patients, with SOFA score 8 [6-12], were prospectively included. Sixty six patients (61%) had sepsis at ICU admission. There was no correlation between plasma citrulline concentration and plasma LPS concentration or activity. However, sepsis at ICU admission was associated with a lower plasma citrulline concentration (13.4 µmol.L-1 vs 21.3 µmol.L-1, p = 0.02). Plasma LPS activity was significantly higher among patients with abdominal sepsis compared to patients with extra-abdominal sepsis (1.04 EU/mL vs 0.63, p = 0.01). CONCLUSIONS: Plasma citrulline is not associated with the level of plasma LPS but is strongly decreased among septic patients. Detection of LPS is ubiquitous among critically ill patients but abdominal sepsis is associated with increased plasma LPS activity compared to extra-abdominal sepsis.


Asunto(s)
Enfermedades Gastrointestinales , Sepsis , Humanos , Lipopolisacáridos , Citrulina , Enfermedad Crítica , Unidades de Cuidados Intensivos
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