Publications by authors named "Isabelle Martins"

87 Publications

Anthocyanins-rich interventions on oxidative stress, inflammation and lipid profile in patients undergoing hemodialysis: meta-analysis and meta-regression.

Eur J Clin Nutr 2022 Jul 12. Epub 2022 Jul 12.

Exercise and Immunometabolism Research Group, Postgraduation Program in Movement Sciences, Department of Physical Education, São Paulo State University (UNESP), Presidente Prudente, São Paulo, Brazil.

The aim of this systematic review and meta-analysis was to evaluate the effects of anthocyanins-interventions on oxidative stress, inflammation, and lipid profile in patients undergoing hemodialysis. This systematic review and meta-analysis were registered on the International Prospective Register of Systematic Reviews (PROSPERO CRD42020209742). The primary outcome was anthocyanins-rich intervention on OS parameters and secondary outcome was anthocyanins-rich intervention on inflammation and dyslipidemia. RevMan 5.4 software was used to analyze the effect size of anthocyanins-rich intervention on OS, inflammation and dyslipidemia. Meta-analysis effect size calculations incorporated random-effects model for both outcomes 1 and 2. Eight studies were included in the systematic review (trials enrolling 715 patients; 165 men and 195 women; age range between 30 and 79 years). Anthocyanin intervention in patients undergoing hemodialysis decrease the oxidant parameters (std. mean: -2.64, 95% CI: [-3.77, -1.50], P ≤ 0.0001, I = 97%). Specially by reduction of malondialdehyde products in favor of anthocyanins-rich intervention (std. mean: -14.58 µmol.L, 95% CI: [-26.20, -2.96], P ≤ 0.0001, I = 99%) and myeloperoxidase (std. mean: -1.28 ηg.mL, 95% CI: [-2.11, -0.45], P = 0.003, I = 77%) against placebo group. Decrease inflammatory parameters (std. mean: -0.57, 95% CI: [-0.98, -0.16], P = 0.007, I = 79%), increase HDL cholesterol levels (std. mean: 0.58 mg.dL, 95% CI: [0.23, 0.94], P = 0.001, I = 12%) against placebo group. Anthocyanins-rich intervention seems to reduce oxidative stress, inflammatory parameters and improve lipid profile by increasing HDL cholesterol levels in patients with chronic kidney disease undergoing hemodialysis.
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http://dx.doi.org/10.1038/s41430-022-01175-6DOI Listing
July 2022

Cancer cell-autonomous overactivation of PARP1 compromises immunosurveillance in non-small cell lung cancer.

J Immunother Cancer 2022 06;10(6)

Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris Cité, Sorbonne Université, Centre de Recherche des Cordeliers, INSERM UMR1138, Paris, France

Background: High activity of poly(ADP-ribose) polymerase-1 (PARP1) in non-small cell lung cancer (NSCLC) cells leads to an increase in immunohistochemically detectable PAR, correlating with poor prognosis in patients with NSCLC, as well as reduced tumor infiltration by cytotoxic T lymphocytes (CTLs). Intrigued by this observation, we decided to determine whether PARP1 activity in NSCLC cells may cause an alteration of anticancer immunosurveillance.

Methods: Continuous culture of mouse NSCLC cells in the presence of cisplatin led to the generation of cisplatin-resistant PAR clones. As compared with their parental controls, such PAR cells formed tumors that were less infiltrated by CTLs when they were injected into immunocompetent mice, suggesting a causative link between high PARP1 activity and compromised immunosurveillance. To confirm this cause-and-effect relationship, we used CRISPR/Cas9 technology to knock out PARP1 in two PAR NSCLC mouse cell lines (Lewis lung cancer [LLC] and tissue culture number one [TC1]), showing that the removal of PARP1 indeed restored cisplatin-induced cell death responses.

Results: PARP1 knockout (PARP1) cells became largely resistant to the PARP inhibitor niraparib, meaning that they exhibited less cell death induction, reduced DNA damage response, attenuated metabolic shifts and no induction of PD-L1 and MHC class-I molecules that may affect their immunogenicity. PAR tumors implanted in mice responded to niraparib irrespective of the presence or absence of T lymphocytes, suggesting that cancer cell-autonomous effects of niraparib dominate over its possible immunomodulatory action. While PAR NSCLC mouse cell lines proliferated similarly in immunocompetent and T cell-deficient mice, PARP1 cells were strongly affected by the presence of T cells. PARP1 LLC tumors grew more quickly in immunodeficient than in immunocompetent mice, and PARP1 TC1 cells could only form tumors in T cell-deficient mice, not in immunocompetent controls. Importantly, as compared with PAR controls, the PARP1 LLC tumors exhibited signs of T cell activation in the immune infiltrate such as higher inducible costimulator (ICOS) expression and lower PD-1 expression on CTLs.

Conclusions: These results prove at the genetic level that PARP1 activity within malignant cells modulates the tumor microenvironment.
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http://dx.doi.org/10.1136/jitc-2021-004280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9247697PMC
June 2022

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABA receptor.

Cell Death Dis 2022 Apr 18;13(4):356. Epub 2022 Apr 18.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.

Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 subunit of gamma-aminobutyric acid A receptor (GABAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAR γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia.
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http://dx.doi.org/10.1038/s41419-022-04834-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016078PMC
April 2022

Autophagy Alteration in ApoA-I Related Systemic Amyloidosis.

Int J Mol Sci 2022 Mar 23;23(7). Epub 2022 Mar 23.

Department of Chemical Sciences, University of Napoli Federico II, Complesso Universitario Monte Sant'Angelo, 80126 Napoli, Italy.

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis.
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http://dx.doi.org/10.3390/ijms23073498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998969PMC
March 2022

Immunization of mice with the self-peptide ACBP coupled to keyhole limpet hemocyanin.

STAR Protoc 2022 03 13;3(1):101095. Epub 2022 Jan 13.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France.

Keyhole limpet hemocyanin (KLH) is a glycosylated multi-subunit metalloprotein that elicits a strong nonspecific immune activation, thus inducing both cellular and humoral immune responses. The exceptional immunogenicity of this protein can be leveraged to vaccinate mice against self-antigens that otherwise would not induce an autoimmune response. This protocol describes the covalent conjugation of KLH with acyl-coenzyme A-binding protein (ACBP), the autovaccination of mice with ACBP-KLH conjugate together with a potent adjuvant, and the detection of the produced anti-ACBP autoantibodies. For complete details on the use and execution of this profile, please refer to Bravo-San Pedro et al. (2019c).
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http://dx.doi.org/10.1016/j.xpro.2021.101095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760546PMC
March 2022

Paradoxical implication of BAX/BAK in the persistence of tetraploid cells.

Cell Death Dis 2021 11 1;12(11):1039. Epub 2021 Nov 1.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.

Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor nocodazole. Mechanistically, in contrast to their BAX/BAK-sufficient controls, tetraploid DKO cells activate a senescent program, as indicated by the overexpression of several cyclin-dependent kinase inhibitors and the activation of β-galactosidase. Moreover, DKO cells manifest alterations in ionomycin-mobilizable endoplasmic reticulum (ER) Ca stores and store-operated Ca entry that are affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca ATPase 2a (Serca2a) and transfection-enforced reintroduction of Serca2a, or reintroduction of an ER-targeted variant of BAK into DKO cells reestablished the same pattern of Ca fluxes as observed in BAX/BAK-sufficient control cells. Serca2a reexpression and ER-targeted BAK also abolished the tetraploidy-induced senescence of DKO cells, placing ER Ca fluxes downstream of the regulation of senescence by BAX/BAK. In conclusion, it appears that BAX/BAK prevent the induction of a tetraploidization-associated senescence program. Speculatively, this may contribute to the low incidence of cancers in BAX/BAK DKO mice and explain why human cancers rarely lose the expression of both BAX and BAK.
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http://dx.doi.org/10.1038/s41419-021-04321-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560871PMC
November 2021

Audiovisual and printed technology to prevent childhood diarrhea: A clinical trial.

Public Health Nurs 2022 03 16;39(2):423-430. Epub 2021 Sep 16.

Federal University of Ceará, Fortaleza, Ceará, Brazil.

Objective: To compare the effect of using an educational booklet and a video alone or together in promoting maternal self-efficacy to prevent childhood diarrhea.

Design And Sample: Randomized multicenter clinical trial with 522 mothers of children under 5 years of age from northeastern Brazil. They were allocated into eight groups, according to the city: metropolis - video alone (N = 61), booklet alone (N = 60), booklet and video along (N = 60), without intervention (N = 60); countryside - booklet alone (N = 70), video alone (N = 70), booklet and video along (N = 71), without intervention (N = 70).

Measurements: A sociodemographic form and the Maternal Self-Efficacy Scale for preventing early childhood diarrhea.

Results: Increases in self-efficacy scores were observed in all experimental groups after the educational intervention. Urban mothers living had greater self-efficacy than rural mothers. This result was verified in the video alone group (p = .036) and without intervention group (p = .003). Mothers in all intervention groups, regardless of the educational intervention used, had higher self-efficacy scores than the comparison group mothers (p < .05).

Conclusion: The tested educational technologies promoted maternal self-efficacy to prevent childhood diarrhea, regardless of whether they are applied alone or in combination.
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http://dx.doi.org/10.1111/phn.12962DOI Listing
March 2022

Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma.

J Exp Med 2021 10 8;218(10). Epub 2021 Sep 8.

Institut National de la Santé et de la Recherche Médicale U1015, Université Paris-Saclay, Gustave Roussy Cancer Campus, Villejuif, France.

Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.
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http://dx.doi.org/10.1084/jem.20200853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429038PMC
October 2021

Multiplexed quantification of autophagic flux by imaging flow cytometry.

Methods Cell Biol 2021 27;165:59-71. Epub 2021 Mar 27.

Centre de Recherche des Cordeliers, Équipe 11 Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. Electronic address:

Imaging flow cytometry allows for the quantitative assessment of fluorescent signals at the subcellular level. Here, we describe the use of a biosensor cell line, namely, U2OS osteosarcoma cells equipped with a fusion protein comprising monomeric red fluorescent protein (mRFP), green fluorescent protein (GFP) and microtubule-associated proteins 1A/1B light chain 3B (best known as LC3), for the assessment of autophagic flux by imaging flow cytometry. We detail all analysis tools required to distinguish autophagosomes (that emit both a red and a green fluorescence) and autolysosomes (that emit a red fluorescence, yet lose the green fluorescent signal) and to quantitate autophagic flux in a convenient fashion.
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http://dx.doi.org/10.1016/bs.mcb.2021.02.005DOI Listing
November 2021

Immunoblot-based assays for assessing autophagy in the turquoise killifish Nothobranchius furzeri.

Methods Cell Biol 2021 18;165:123-138. Epub 2020 Nov 18.

Centre de Recherche des Cordeliers, Équipe 11 Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Autophagy is an evolutionarily conserved biological process required for the turnover of the cytoplasm of eukaryotic cell. Beyond its catabolic nature, autophagy has a plethora of pro-survival functions, thus combatting hypoxia, nutrient shortage, and unfolded protein accumulation. Here, we introduce the naturally short-lived turquoise killifish Nothobranchius furzeri as an emerging model to study autophagic function in vivo, in response to environmental challenges. We show that starvation in killifish is sufficient to increase autophagic flux in the liver, thus enhancing the lipidation of microtubule-associated protein light chain 3 (LC3) and reducing the abundance of the autophagic substrate sequestosome-1 (SQSTM1). We describe an immunoblot-based comprehensive protocol to monitor fluctuations in autophagy in this model organism.
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http://dx.doi.org/10.1016/bs.mcb.2020.10.007DOI Listing
November 2021

Quantification of intracellular ACBP/DBI levels.

Methods Cell Biol 2021 13;165:111-122. Epub 2021 Jan 13.

Center for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain. Electronic address:

Acyl-CoA binding protein (ACBP), also called diazepam-binding inhibitor (DBI), is a ubiquitous protein that can be secreted from cells by an unconventional pathway. Depending on its levels and on its subcellular localization, ACBP/DBI can regulate lipid metabolism. Several studies have shown that ACBP/DBI is secreted by an autophagy-dependent mechanism, positioning this catabolic pathway as the mechanism that controls lipid metabolism through the intracellular modulation of the levels of this protein. Autophagy is activated, among other stimuli, when cells have increased energy requirements; this causes a drop in the intracellular ACBP/DBI levels due to its release into the extracellular space and triggers an increase in the lipid catabolism. Conversely, when autophagy is inhibited, during pathological (obesity) or physiological (after-meal) situations, the intracellular levels of ACBP/DBI increase resulting in the activation of lipid anabolism, this effect has been demonstrated to be the link between obesity and autophagy inhibition. Here, we detail three different protocols for the detection of the ACBP/DBI levels by immunofluorescence, image flow cytometry or immunoblot techniques, which allow the quantification of ACBP/DBI levels and, indirectly, its autophagy-dependent release.
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http://dx.doi.org/10.1016/bs.mcb.2020.12.004DOI Listing
November 2021

Elevated plasma levels of the appetite-stimulator ACBP/DBI in fasting and obese subjects.

Cell Stress 2021 Jul 28;5(7):89-98. Epub 2021 Jun 28.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université de Paris, Sorbonne Université, Paris, France.

Eukaryotic cells release the phylogenetically ancient protein acyl coenzyme A binding protein (ACBP, which in humans is encoded by the gene DBI, diazepam binding inhibitor) upon nutrient deprivation. Accordingly, mice that are starved for one to two days and humans that undergo voluntary fasting for one to three weeks manifest an increase in the plasma concentration of ACBP/DBI. Paradoxically, ACBP/DBI levels also increase in obese mice and humans. Since ACBP/DBI stimulates appetite, this latter finding may explain why obesity constitutes a self-perpetuating state. Here, we present a theoretical framework to embed these findings in the mechanisms of weight control, as well as a bioinformatics analysis showing that, irrespective of the human cell or tissue type, one single isoform of ACBP/DBI (ACBP1) is preponderant (~90% of all DBI transcripts, with the sole exception of the testis, where it is ~70%). Based on our knowledge, we conclude that ACBP1 is subjected to a biphasic transcriptional and post-transcriptional regulation, explaining why obesity and fasting both are associated with increased circulating ACBP1 protein levels.
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http://dx.doi.org/10.15698/cst2021.07.252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283301PMC
July 2021

Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects.

Cell Death Dis 2021 07 16;12(8):713. Epub 2021 Jul 16.

Centre de Recherche des Cordeliers, INSERM UMRS1138, Université de Paris, Sorbonne Université, Team "Metabolism, Cancer & Immunity", 75006, Paris, France.

Immunogenic cell death (ICD) is clinically relevant because cytotoxicants that kill malignant cells via ICD elicit anticancer immune responses that prolong the effects of chemotherapies beyond treatment discontinuation. ICD is characterized by a series of stereotyped changes that increase the immunogenicity of dying cells: exposure of calreticulin on the cell surface, release of ATP and high mobility group box 1 protein, as well as a type I interferon response. Here, we examined the possibility that inhibition of an oncogenic kinase, anaplastic lymphoma kinase (ALK), might trigger ICD in anaplastic large cell lymphoma (ALCL) in which ALK is activated due to a chromosomal translocation. Multiple lines of evidence plead in favor of specific ICD-inducing effects of crizotinib and ceritinib in ALK-dependent ALCL: (i) they induce ICD stigmata at pharmacologically relevant, low concentrations; (ii) can be mimicked in their ICD-inducing effects by ALK knockdown; (iii) lose their effects in the context of resistance-conferring ALK mutants; (iv) ICD-inducing effects are mimicked by inhibition of the signal transduction pathways operating downstream of ALK. When ceritinib-treated murine ALK-expressing ALCL cells were inoculated into the left flank of immunocompetent syngeneic mice, they induced an immune response that slowed down the growth of live ALCL cells implanted in the right flank. Although ceritinib induced a transient shrinkage of tumors in lymphoma-bearing mice, irrespective of their immunocompetence, relapses occurred more frequently in the context of immunodeficiency, reducing the effects of ceritinib on survival by approximately 50%. Complete cure only occurred in immunocompetent mice and conferred protection to rechallenge with the same ALK-expressing lymphoma but not with another unrelated lymphoma. Moreover, immunotherapy with PD-1 blockade tended to increase cure rates. Altogether, these results support the contention that specific ALK inhibition stimulates the immune system by inducing ICD in ALK-positive ALCL.
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http://dx.doi.org/10.1038/s41419-021-03997-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285454PMC
July 2021

The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma.

Blood 2022 01;139(3):384-398

Université de Paris, NF-κB, Différenciation et Cancer, Paris, France.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. The NF-κB transcription factor family is activated by 2 main pathways, the canonical and the alternative NF-κB activation pathway, with different functions. The alternative NF-κB pathway leads to activation of the transcriptionally active RelB NF-κB subunit. Alternative NF-κB activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their activated B-cell-like or germinal center B-cell-like subtype. RelB activity defines a new subset of patients with DLBCL and a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for activated B-cell-like tumors carrying MYD88L265P and CD79B mutations that cooperatively activate canonical NF-κB, thus indicating that current genetic tools to evaluate NF-κB activity in DLBCL do not provide information on the alternative NF-κB activation. Furthermore, the newly defined RelB-positive subgroup of patients with DLBCL exhibits a dismal outcome after immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA damage-induced apoptosis in response to doxorubicin, a genotoxic agent used in the front-line treatment of DLBCL. We also show that RelB positivity is associated with high expression of cellular inhibitor of apoptosis protein 2 (cIAP2). Altogether, RelB activation can be used to refine the prognostic stratification of DLBCL and may contribute to subvert the therapeutic DNA damage response in a segment of patients with DLBCL.
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http://dx.doi.org/10.1182/blood.2020010039DOI Listing
January 2022

Effects of acyl-coenzyme A binding protein (ACBP)/diazepam-binding inhibitor (DBI) on body mass index.

Cell Death Dis 2021 06 9;12(6):599. Epub 2021 Jun 9.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université de Paris, Sorbonne Université, Paris, France.

In mice, the plasma concentrations of the appetite-stimulatory and autophagy-inhibitory factor acyl-coenzyme A binding protein (ACBP, also called diazepam-binding inhibitor, DBI) acutely increase in response to starvation, but also do so upon chronic overnutrition leading to obesity. Here, we show that knockout of Acbp/Dbi in adipose tissue is sufficient to prevent high-fat diet-induced weight gain in mice. We investigated ACBP/DBI plasma concentrations in several patient cohorts to discover a similar dual pattern of regulation. In relatively healthy subjects, ACBP/DBI concentrations independently correlated with body mass index (BMI) and age. The association between ACBP/DBI and BMI was lost in subjects that underwent major weight gain in the subsequent 3-9 years, as well as in advanced cancer patients. Voluntary fasting, undernutrition in the context of advanced cancer, as well as chemotherapy were associated with an increase in circulating ACBP/DBI levels. Altogether, these results support the conclusion that ACBP/DBI may play an important role in body mass homeostasis as well as in its failure.
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http://dx.doi.org/10.1038/s41419-021-03864-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190068PMC
June 2021

Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response.

Cell Death Dis 2021 01 6;12(1). Epub 2021 Jan 6.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.

The integrated stress response manifests with the phosphorylation of eukaryotic initiation factor 2α (eIF2α) on serine residue 51 and plays a major role in the adaptation of cells to endoplasmic reticulum stress in the initiation of autophagy and in the ignition of immune responses. Here, we report that lysosomotropic agents, including azithromycin, chloroquine, and hydroxychloroquine, can trigger eIF2α phosphorylation in vitro (in cultured human cells) and, as validated for hydroxychloroquine, in vivo (in mice). Cells bearing a non-phosphorylatable eIF2α mutant (S51A) failed to accumulate autophagic puncta in response to azithromycin, chloroquine, and hydroxychloroquine. Conversely, two inhibitors of eIF2α dephosphorylation, nelfinavir and salubrinal, enhanced the induction of such autophagic puncta. Altogether, these results point to the unexpected capacity of azithromycin, chloroquine, and hydroxychloroquine to elicit the integrated stress response.
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http://dx.doi.org/10.1038/s41419-020-03324-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790317PMC
January 2021

Autophagy-mediated metabolic effects of aspirin.

Cell Death Discov 2020 Nov 24;6(1):129. Epub 2020 Nov 24.

Karolinska Institute, Department of Bioscience and Nutrition, Huddinge, Sweden.

Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b or Bcln1) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.
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http://dx.doi.org/10.1038/s41420-020-00365-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687910PMC
November 2020

Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene.

Cell Death Differ 2021 05 30;28(5):1477-1492. Epub 2020 Nov 30.

Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Descartes, Université Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.

Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.
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http://dx.doi.org/10.1038/s41418-020-00672-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166836PMC
May 2021

A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

Cancer Discov 2021 02 12;11(2):408-423. Epub 2020 Oct 12.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of , calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of . These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in , harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking , suggesting a personalized strategy for compensating for the FPR1 defect..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0465DOI Listing
February 2021

Ganglion cells and displaced amacrine cells density in the retina of the collared peccary (Pecari tajacu).

PLoS One 2020 1;15(10):e0239719. Epub 2020 Oct 1.

Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Pará, Brasil.

In the present study, we investigated the topographical distribution of ganglion cells and displaced amacrine cells in the retina of the collared peccary (Pecari tajacu), a diurnal neotropical mammal of the suborder Suina (Order Artiodactyla) widely distributed across central and mainly South America. Retinas were prepared and processed following the Nissl staining method. The number and distribution of retinal ganglion cells and displaced amacrine cells were determined in six flat-mounted retinas from three animals. The average density of ganglion cells was 351.822 ± 31.434 GC/mm2. The peccary shows a well-developed visual streak. The average peak density was 6,767 GC/mm2 and located within the visual range and displaced temporally as an area temporalis. Displaced amacrine cells have an average density of 300 DAC/mm2, but the density was not homogeneous along the retina, closer to the center of the retina the number of cells decreases and when approaching the periphery the density increases, in addition, amacrine cells do not form retinal specialization like ganglion cells. Outside the area temporalis, amacrine cells reach up to 80% in the ganglion cell layer. However, in the region of the area temporalis, the proportion of amacrine cells drops to 32%. Thus, three retinal specializations were found in peccary's retina by ganglion cells: visual streak, area temporalis and dorsotemporal extension. The topography of the ganglion cells layer in the retina of the peccary resembles other species of Order Artiodactyla already described and is directly related to its evolutionary history and ecology of the species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239719PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529232PMC
November 2020

Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI).

Cell Death Dis 2020 07 6;11(7):502. Epub 2020 Jul 6.

Fondation FondaMental, Créteil, France.

Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI) is a multifunctional protein with an intracellular action (as ACBP), as well as with an extracellular role (as DBI). The plasma levels of soluble ACBP/DBI are elevated in human obesity and reduced in anorexia nervosa. Accumulating evidence indicates that genetic or antibody-mediated neutralization of ACBP/DBI has anorexigenic effects, thus inhibiting food intake and inducing lipo-catabolic reactions in mice. A number of anorexiants have been withdrawn from clinical development because of their side effects including an increase in depression and suicide. For this reason, we investigated the psychiatric impact of ACBP/DBI in mouse models and patient cohorts. Intravenously (i.v.) injected ACBP/DBI protein conserved its orexigenic function when the protein was mutated to abolish acyl coenzyme A binding, but lost its appetite-stimulatory effect in mice bearing a mutation in the γ2 subunit of the γ-aminobutyric acid (GABA) A receptor (GABAR). ACBP/DBI neutralization by intraperitoneal (i.p.) injection of a specific mAb blunted excessive food intake in starved and leptin-deficient mice, but not in ghrelin-treated animals. Neither i.v. nor i.p. injected anti-ACBP/DBI antibody affected the behavior of mice in the dark-light box and open-field test. In contrast, ACBP/DBI increased immobility in the forced swim test, while anti-ACBP/DBI antibody counteracted this sign of depression. In patients diagnosed with therapy-resistant bipolar disorder or schizophrenia, ACBP/DBI similarly correlated with body mass index (BMI), not with the psychiatric diagnosis. Patients with high levels of ACBP/DBI were at risk of dyslipidemia and this effect was independent from BMI, as indicated by multivariate analysis. In summary, it appears that ACBP/DBI neutralization has no negative impact on mood and that human depression is not associated with alterations in ACBP/DBI concentrations.
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http://dx.doi.org/10.1038/s41419-020-2716-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338362PMC
July 2020

Triarylpyridine Compounds and Chloroquine Act in Concert to Trigger Lysosomal Membrane Permeabilization and Cell Death in Cancer Cells.

Cancers (Basel) 2020 Jun 18;12(6). Epub 2020 Jun 18.

Institut Bergonié, INSERM U1218, Université de Bordeaux, 33000 Bordeaux, France.

Lysosomes play a key role in regulating cell death in response to cancer therapies, yet little is known on the possible role of lysosomes in the therapeutic efficacy of G-quadruplex DNA ligands (G4L) in cancer cells. Here, we investigate the relationship between the modulation of lysosomal membrane damage and the degree to which cancer cells respond to the cytotoxic effects of G-quadruplex ligands belonging to the triarylpyridine family. Our results reveal that the lead compound of this family, promotes the enlargement of the lysosome compartment as well as the induction of lysosome-relevant mRNAs. Interestingly, the combination of and chloroquine (an inhibitor of lysosomal functions) led to a significant induction of lysosomal membrane permeabilization coupled to massive cell death. Similar effects were observed when chloroquine was added to three new triarylpyridine derivatives. Our findings thus uncover the lysosomal effects of triarylpyridines compounds and delineate a rationale for combining these compounds with chloroquine to increase their anticancer effects.
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http://dx.doi.org/10.3390/cancers12061621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352983PMC
June 2020

Antibody-mediated neutralization of ACBP/DBI has anorexigenic and lipolytic effects.

Adipocyte 2020 12;9(1):116-119

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.

We recently identified acyl coenzyme A-binding protein (ACBP)/diazepam binding inhibitor (DBI) as a novel 'hunger factor': a protein that is upregulated in human or murine obesity and that, if administered to mice, causes hyperphagy, adipogenesis and obesity. Conversely, neutralization of ACBP/DBI by systemic injection of neutralizing monoclonal antibodies or autoantibodies produced after auto-immunization against ACBP/DBI has anorexigenic and lipolytic effects. Thus, neutralization of ACBP/DBI results in reduced food intake subsequent to the activation of anorexigenic neurons and the inactivation of orexigenic neurons in the hypothalamus. Moreover, ACBP/DBI neutralization results into enhanced triglyceride lipolysis in white fat, a surge in free fatty acids in the plasma, enhanced incorporation of glycerol-derived carbon atoms into glucose, as well as an increase in β-oxidation, resulting in a net reduction of fat mass. Importantly, ACBP/DBI neutralization also stimulated an increase in autophagy in various organs, suggesting that it might mediate anti-ageing effects.
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http://dx.doi.org/10.1080/21623945.2020.1736734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153538PMC
December 2020

Quantitative determination of phagocytosis by bone marrow-derived dendritic cells via imaging flow cytometry.

Methods Enzymol 2020 2;632:27-37. Epub 2019 Aug 2.

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Faculté de Medicine, Université Paris Saclay/Paris XI, Le Kremlin-Bicêtre, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Immunogenic cell death (ICD), induced by certain anticancer chemotherapeutics, leads to the emission of danger associated molecular patterns (DAMP) by cancer cells, which facilitates the attraction, activation and maturation of dendritic cells (DC) as well as the subsequent priming of effector T cells. In this context calreticulin (CALR) exposed at an early stage of ICD at the surface of the cancer cells serves as phagocytic signal and triggers the formation of immunological synapses between malignant cells and DC. Subsequent phagocytosis facilitates the transfer of tumor associated antigen and thus depicts a fundamental step in the generation of anticancer immunity. Here we provide an imaging flowcytometric protocol for the quantification of ICD-associated DC phagocytosis of cancer cells. As compared to the traditional flowcytometry-based analysis, the presented method offers additional means of differentiation between the transient formation of immunological synapses and the final DC-mediated phagocytosis of cancer cells.
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http://dx.doi.org/10.1016/bs.mie.2019.07.021DOI Listing
December 2020

Immunosuppression by Mutated Calreticulin Released from Malignant Cells.

Mol Cell 2020 02 27;77(4):748-760.e9. Epub 2019 Nov 27.

Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMR 1138, Paris, France; Sorbonne Université, Paris, France; Université of Paris, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China; Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. Electronic address:

Mutations affecting exon 9 of the CALR gene lead to the generation of a C-terminally modified calreticulin (CALR) protein that lacks the KDEL endoplasmic reticulum (ER) retention signal and consequently mislocalizes outside of the ER where it activates the thrombopoietin receptor in a cell-autonomous fashion, thus driving myeloproliferative diseases. Here, we used the retention using selective hooks (RUSH) assay to monitor the trafficking of CALR. We found that exon-9-mutated CALR was released from cells in response to the biotin-mediated detachment from its ER-localized hook, in vitro and in vivo. Cellular CALR release was confirmed in suitable mouse models bearing exon-9-mutated hematopoietic systems or tumors. Extracellular CALR mediated immunomodulatory effects and inhibited the phagocytosis of dying cancer cells by dendritic cells (DC), thereby suppressing antineoplastic immune responses elicited by chemotherapeutic agents or by PD-1 blockade. Altogether, our results demonstrate paracrine immunosuppressive effects for exon-9-mutated CALR.
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http://dx.doi.org/10.1016/j.molcel.2019.11.004DOI Listing
February 2020

Spatial frequency selectivity of the human visual cortex estimated with pseudo-random visual evoked cortical potential (VECP).

Vision Res 2019 12 11;165:13-21. Epub 2019 Oct 11.

Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Pará, Brazil; Núcleo de Medicina Tropical, Universidade Federal do Pará, Belém, Pará, Brazil; Universidade do Ceuma, São Luís, Maranhão, Brazil. Electronic address:

Single-cell recordings in the primary visual cortex (V1) show neurons with spatial frequency (SF) tuning, which had different responses to chromatic and luminance stimuli. Visually evoked cortical potential (VECP) investigations have reported different spatial profiles. The current study aimed to investigate the spatial selectivity of V1 to simultaneous stimulus of chromatic and luminance contrasts. Compound stimuli temporally driven by m-sequences at 8 SFs were utilized to generate VECP records from thirty subjects (14 trichromats and 16 colorblind subjects). We extracted the second-order kernel, first and second slices (K2.1 and K2.2, respectively). Optimal SF, SF bandwidth, and high SF cut-off were estimated from the best-fitted functions to the VECP amplitude vs SF. For trichromats, K2.1 waveforms had a negative component (N1 K2.1) at 100 ms followed by a positive component (P1 K2.1). K2.2 waveforms also had a negative component (N1 K2.2) at 100 ms followed by a positive deflection (P1 K2.2). SF tuning of N1 K2.1 and N1 K2.2 had a band-pass profile, while the P1 K2.1 was low-pass tuned. P1 K2.1 optimal SF differed significantly from both other negative responses and from P1 K2.2. We found differences in the optimal SF, SF tuning and high SF cut-off among the VECP components. Dichromats had little or no response for all stimulus conditions. The absence of the responses in dichromats, the similarity between the high SF cut-off of the pseudorandom VECPs and psychophysical chromatic visual acuity, and presence of multiple SF tunings suggested that pseudorandom VECPs represented the activity of cells that responded preferentially to the chromatic component of the compound stimuli.
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http://dx.doi.org/10.1016/j.visres.2019.09.004DOI Listing
December 2019

Cell-autonomous, paracrine and neuroendocrine feedback regulation of autophagy by DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein): the obesity factor.

Autophagy 2019 11 5;15(11):2036-2038. Epub 2019 Sep 5.

Centre de Recherche des Cordeliers, Inserm U1138, Université de Paris, Sorbonne Université , Paris , France.

DBI/ACBP (diazepam binding protein, acyl-CoA binding protein) participates in the regulation of fatty acid metabolism when it is localized within cells, whereas outside of cells it acts as a diazepam-binding protein. Recent results indicate that many different mammalian cell types release DBI/ACBP upon or starvation in a macroautophagy/autophagy-dependent fashion. The autophagy-associated release of DBI/ACBP elicits feedback inhibition of autophagy through 3 independent mechanisms. First, the depletion of DBI/ACBP from cells limits autophagy in a cell-autonomous fashion. Second, extracellular DBI/ACBP acts in a paracrine fashion to inhibit autophagy. Third, DBI/ACBP increasing in the systemic circulation acts as an activator of lipo-anabolism and feeding behavior, thus removing the cause of autophagy induction (starvation) and suppressing the phenomenon. DBI/ACBP expression is upregulated at the mRNA and protein levels in obese mice and humans, and its extracellular neutralization by antibodies controls food intake and increases lipo-catabolism. Current data support the contention that DBI/ACBP is an important pro-obesity factor. : DBI: diazepam binding protein, acyl-CoA binding protein; GABR: gamma-aminobutyric acid type A receptor; TSPO: translocator protein.
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http://dx.doi.org/10.1080/15548627.2019.1662585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844558PMC
November 2019

Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity.

Cell Metab 2019 10 15;30(4):754-767.e9. Epub 2019 Aug 15.

Université of Paris, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.

Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities.
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http://dx.doi.org/10.1016/j.cmet.2019.07.010DOI Listing
October 2019
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