Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation.

Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.S

Apolipoprotein mimetics in cancer

Peptides have many advantages over traditional therapeutics, including small molecules and other biologics, because of their low toxicity and immunogenicity, while still exhibiting efficacy. This review discusses the benefits and mechanism of action of apolipoprotein mimetic peptides in tumor biology and their potential utility in treating various cancers. Among lipoproteins in the circulation, high-density lipoprotein (HDL) and its constituents including apolipoprotein A-I (apoA-I; the predominant protein in HDL), apoJ, and apoE, harbor anti-tumorigenic activities. Peptides that mimic apoA-I function have been developed through molecular mimicry of the amphipathic α-helices of apoA-I. Oral apoA-I mimetic peptides remodel HDL, promote cholesterol efflux, sequester oxidized lipids, and activate anti-inflammatory processes. ApoA-I and apoJ mimetic peptides ameliorate various metrics of cancer progression and have demonstrated efficacy in preclinical models in the inhibition of ovarian, colon, breast, and metastatic lung cancers. Apolipoprotein mimetic peptides are poorly absorbed when administered orally and rapidly degraded when injected into the circulation. The small intestine is the major site of action for apoA-I mimetic peptides and recent studies suggest that modulation of immune cells in the lamina propria of the small intestine is, in part, a potential mechanism of action. Finally, several recent studies underscore the use of reconstituted HDL as target-specific nanoparticles carrying poorly soluble or unstable therapeutics to tumors even across the blood-brain barrier. Preclinical studies suggest that these versatile recombinant lipoprotein based nanoparticles and apolipoprotein mimetics can serve as safe, novel drug delivery, and therapeutic agents for the treatment of a number of cancers.This work was supported in part by US Public Health Service Research Grants 1R01 HL148286, P01HL030568, R01HL071776, R01HL123064, and R01HL129051, and the Laubisch, Castera, and M.K. Grey Funds at the University of California at Los Angeles

Altered Brain Metabolome Is Associated with Memory Impairment in the rTg4510 Mouse Model of Tauopathy

© 2020 by the authors.Alzheimer’s disease (AD) is characterized, amongst other features, by the pathologic accumulation of abnormally phosphorylated tau filaments in neurons that lead to neurofibrillary tangles. However, the molecular mechanisms by which the abnormal processing of tau leads to neurodegeneration and cognitive impairment remain unknown. Metabolomic techniques can comprehensively assess disturbances in metabolic pathways that reflect changes downstream from genomic, transcriptomic and proteomic systems. In the present study, we undertook a targeted metabolomic approach to determine a total of 187 prenominated metabolites in brain cortex tissue from wild type and rTg4510 animals (a mice model of tauopathy), in order to establish the association of metabolic pathways with cognitive impairment. This targeted metabolomic approach revealed significant differences in metabolite concentrations of transgenic mice. Brain glutamine, serotonin and sphingomyelin C18:0 were found to be predictors of memory impairment. These findings provide informative data for future research on AD, since some of them agree with pathological alterations observed in diseased humans.This research was funded by Fundación Alfonso Martín Escudero (2014), Spain (awarded to MT). and a grant from the Juan de la Cierva-Incorporación, Ministerio de Economía y Competitividad (IJCI-2016-29393), Spain (awarded to DdG-C).Peer reviewe

MDA-LDL vaccination induces athero-protective germinal-center-derived antibody responses.

Atherosclerosis is a chronic inflammatory disease of the arteries that can lead to thrombosis, infarction, and stroke and is the leading cause of mortality worldwide. Immunization of pro-atherogenic mice with malondialdehyde-modified low-density lipoprotein (MDA-LDL) neo-antigen is athero-protective. However, the immune response to MDA-LDL and the mechanisms responsible for this athero-protection are not completely understood. Here, we find that immunization of mice with MDA-LDL elicits memory B cells, plasma cells, and switched anti-MDA-LDL antibodies as well as clonal expansion and affinity maturation, indicating that MDA-LDL triggers a bona fide germinal center antibody response. Further, Prdm1fl/flAicda-Cre+/kiLdlr-/- pro-atherogenic chimeras, which lack germinal center-derived plasma cells, show accelerated atherosclerosis. Finally, we show that MDA-LDL immunization is not athero-protective in mice lacking germinal-center-derived plasma cells. Our findings give further support to the development of MDA-LDL-based vaccines for the prevention or treatment of atherosclerosis.We thank all members of the B Cell Biology Laboratory for useful discussions, A. Rodriguez-Ronchel for the design of the graphical abstract, V.G. de Ye´benes for critical reading of the manuscript, and V. Labrador for help with microscopy and image analysis. I.M.-F. and C.L. were fellows of the research training program funded by Ministerio de Economı´a y Competitividad (SVP-2014-068216 and SVP-2014-068289, respectively), A.d.M.M. is funded by ‘‘la Caixa’’ Foundation HR17–00247, and A.R.R. was supported by Centro Nacional de Investigaciones Cardiovasculares (CNIC). The project leading to these results has received funding from la Caixa Banking Foundation under the project code HR17-00247 and from SAF2016-75511-R and PID2019-106773RB-I00/AEI/10.13039/501100 011033 grants to A.R.R. (Plan Estatal de Investigacio´ n Cientı´fica y Te´ cnica y de Innovacio´ n 2013–2016 Programa Estatal de I+D+i Orientada a los Retos de la Sociedad Retos Investigacio´ n: Proyectos I + D + i 2016, Ministerio de Economı´a,Industria y Competitividad) and co-funding by Fondo Europeo de Desarrollo Regional (FEDER). CIBERCV (J.L.M.-V.) and CIBERDEM (J.C.E.-G.) are Instituto de Salud Carlos III projects. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovacio´ n (MCIN), and the Pro CNIC Foundation and is a Severo Ochoa institute (CEX2020-001041-S grant funded by MCIN/AEI/10.13039/501100011033).S

Obesity-induced hepatic steatosis in mice is reverted by AAV9-mediated enhanced fatty-acid oxidation

Trabajo presentado en la 52nd Annual Scientifi Meeting of the European Society for Clinical Investigation (ESCI), celebrada en Barcelona, del miércoles, 30 de mayo de 2018 hasta el viernes, 1 de junio de 2018[Background] Obesity‐induced insulin resistance is associated, among others, with both ectopic lipid deposition and chronic, low‐grade adipose tissue inflammation. Despite the excess of fat, obese individuals show lower fatty‐acid oxidation rates. Thus, burning off the excess of fat could improve the obese metabolic phenotype. The aim of the present study was to evaluate the therapeutic potential of adenoassociated viruses (AAV) 9‐mediated liver expression of a human malonyl‐CoA‐insensitive carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in fatty‐acid β‐oxidation (FAO), in a diet‐induced obese mouse model.[Materials and methods] We analyzed the metabolic and physiological effects of the long‐term liver hCPT1AM expression and the enhanced FAO on the diet‐induced obese mice.[Results] The enhanced hepatic FAO resulted in the reversion of the obese phenotype reducing body weight, hyperglycemia, hyperinsulinemia and hepatic steatosis. The mechanism involved are the hepatic activation of autophagy, lipolysis, cholesterol mobilization and energy dissipation by increasing liver temperature and the production of CO2, ATP and ketone bodies. Notably, the increase in hepatic FAO produced deep changes in the hepatic and serum lipidomic profile pointing out some ceramide and phosphatidylcholine species as potential markers for obesity reversion and hepatic steatosis improvement.[Conclusion] An increase in liver FAO improves the obese metabolic phenotype, which indicates that AAV9‐mediated hCPT1AM expression could be a potential molecular therapy for obesity and diabetes.Peer reviewe

Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response

International audienceBackgroundAntibodies against the P3 sequence (Gly1127-Cys1140) of LRP1 (anti-P3 Abs) specifically block cholesteryl ester (CE) accumulation in vascular cells. LRP1 is a key regulator of insulin receptor (InsR) trafficking in different cell types. The link between CE accumulation and the insulin response are largely unknown. Here, the effects of P3 peptide immunization on the alterations induced by a high-fat diet (HFD) in cardiac insulin response were evaluated.MethodsIrrelevant (IrP)- or P3 peptide-immunized rabbits were randomized into groups fed either HFD or normal chow. Cardiac lipid content was characterized by thin-layer chromatography, confocal microscopy, and electron microscopy. LRP1, InsR and glucose transporter type 4 (GLUT4) levels were determined in membranes and total lysates from rabbit heart. The interaction between InsR and LRP1 was analyzed by immunoprecipitation and confocal microscopy. Insulin signaling activity and glucose uptake were evaluated in HL-1 cells exposed to rabbit serum from the different groups.FindingsHFD reduces cardiac InsR and GLUT4 membrane levels and the interactions between LRP1/InsR. Targeting the P3 sequence on LRP1 through anti-P3 Abs specifically reduces CE accumulation in the heart independently of changes in the circulating lipid profile. This restores InsR and GLUT4 levels in cardiac membranes as well as the LRP1/InsR interactions of HFD-fed rabbits. In addition, anti-P3 Abs restores the insulin signaling cascade and glucose uptake in HL-1 cells exposed to hypercholesterolemic rabbit serum