Publications by authors named "Bart Staels"

539 Publications

Intestine-Liver Cross-talk in Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease.

Metabolism 2021 Jul 31:154844. Epub 2021 Jul 31.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France. Electronic address:

Type 2 diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD) are pathologies whose prevalence continues to increase worldwide. Both diseases are precipitated by an excessive caloric intake, which promotes insulin resistance and fatty liver. The role of the intestine and its crosstalk with the liver in the development of these metabolic diseases is receiving increasing attention. Alterations in diet-intestinal microbiota interactions lead to the dysregulation of intestinal functions, resulting in altered metabolite and energy substrate production and increased intestinal permeability. Connected through the portal circulation, these changes in intestinal functions impact the liver and other metabolic organs, such as visceral adipose tissue, hence participating in the development of insulin resistance, and worsening T2D and NAFLD. Thus, targeting the intestine may be an efficient therapeutic approach to cure T2D and NAFLD. In this review, we will first introduce the signaling pathways linking T2D and NAFLD. Next, we will address the role of the gut-liver crosstalk in the development of T2D and NAFLD, with a particular focus on the gut microbiota and the molecular pathways behind the increased intestinal permeability and inflammation. Finally, we will summarize the therapeutic strategies which target the gut and its functions and are currently used or under development to treat T2D and NAFLD.
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http://dx.doi.org/10.1016/j.metabol.2021.154844DOI Listing
July 2021

An optimized protocol with a stepwise approach to identify specific nuclear receptor ligands from cultured mammalian cells.

STAR Protoc 2021 Sep 7;2(3):100658. Epub 2021 Jul 7.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France.

Here, we describe an optimized protocol to identify specific nuclear receptor ligands. First, to rule out any compound interference with luciferase activity per se, we describe an assay assessing potential inhibition or activation of luciferase enzymatic activity. Second, to comply with EMA and FDA guidelines to mitigate drug-drug interactions, we detail assays assessing constitutive androstane receptor (CAR) and pregnane X receptor (PXR) activation ability. Finally, to minimize off-target detection effects, we describe the use of mammalian one- (or two-) hybrid systems. For complete details on the use and execution of this protocol, please refer to Hering et al. (2018).
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http://dx.doi.org/10.1016/j.xpro.2021.100658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273406PMC
September 2021

Why is elevation of serum cholesterol associated with exposure to perfluoroalkyl substances (PFAS) in humans? A workshop report on potential mechanisms.

Toxicology 2021 Jul 8;459:152845. Epub 2021 Jul 8.

Ramboll US Consulting, Inc., 3214 Charles B. Root Wynd, Suite 130, Raleigh, NC 27612, USA. Electronic address:

Serum concentrations of cholesterol are positively correlated with exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) in humans. The associated change in cholesterol is small across a broad range of exposure to PFOA and PFOS. Animal studies generally have not indicated a mechanism that would account for the association in humans. The extent to which the relationship is causal is an open question. Nonetheless, the association is of particular importance because increased serum cholesterol has been considered as an endpoint to derive a point of departure in at least one recent risk assessment. To gain insight into potential mechanisms for the association, both causal and non-causal, an expert workshop was held Oct 31 and Nov 1, 2019 to discuss relevant data and propose new studies. In this report, we summarize the relevant background data, the discussion among the attendees, and their recommendations for further research.
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http://dx.doi.org/10.1016/j.tox.2021.152845DOI Listing
July 2021

Regulation of PPARα by APP in Alzheimer disease impacts the pharmacological modulation of synaptic activity.

JCI Insight 2021 Jul 6. Epub 2021 Jul 6.

Institute of Neuroscience, UCLouvain, Brussels, Belgium.

Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in AD physiopathology impairs lipid synthesis needed for cortical networks activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation are inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains. Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by PPARα specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process.
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http://dx.doi.org/10.1172/jci.insight.150099DOI Listing
July 2021

PPAR control of metabolism and cardiovascular functions.

Nat Rev Cardiol 2021 Jun 14. Epub 2021 Jun 14.

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.

Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.
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http://dx.doi.org/10.1038/s41569-021-00569-6DOI Listing
June 2021

Day-Time Declamping Is Associated with Better Outcomes in Kidney Transplantation: The Circarein Study.

J Clin Med 2021 May 26;10(11). Epub 2021 May 26.

CHU Lille, 59000 Lille, France.

Despite improvements in organ preservation techniques and efforts to minimize the duration of cold ischemia, ischemia-reperfusion (IR) injury remains associated with poor graft function and long-term survival in kidney transplantation. We recently demonstrated a clinically significant day-time variation in myocardial tolerance to IR, transcriptionally orchestrated by the circadian clock. Patient and graft post-transplant survival were studied in a cohort of 10,291 patients first transplanted between 2006 and 2017 to test whether kidney graft tolerance to IR depends on the time-of-the-day of clamping/declamping, and thus impacts graft and patient survival. Post-transplant 1- and 3-year survival decreased with increasing ischemia duration. Time-of-the-day of clamping did not influence outcomes. However, night-time (vs. day-time) declamping was associated with a significantly worse post-transplant survival. After adjustment for other predictors, night-time (vs. day-time) declamping remained associated with a worse 1-year (HR = 1.26 (1.08-1.47), = 0.0028 by Cox multivariable analysis) and 3-year (HR = 1.14 (1.02-1.27), = 0.021) outcome. Interestingly, the deleterious impact of prolonged ischemia time (>15 h) was partially compensated by day-time (vs. night-time) declamping. Compared to night-time declamping, day-time declamping was associated with a better prognosis of kidney transplantation despite a longer duration of cold ischemia.
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http://dx.doi.org/10.3390/jcm10112322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198093PMC
May 2021

IFNγ-producing NK cells in adipose tissue are associated with hyperglycemia and insulin resistance in obese women.

Int J Obes (Lond) 2021 Jul 1;45(7):1607-1617. Epub 2021 May 1.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.

Background/objectives: Innate lymphoid cells (ILCs) play an important role in the maintenance of immune and metabolic homeostasis in adipose tissue (AT). The crosstalk between AT ILCs and adipocytes and other immune cells coordinates adipocyte differentiation, beiging, glucose metabolism and inflammation. Although the metabolic and homeostatic functions of mouse ILCs have been extensively investigated, little is known about human adipose ILCs and their roles in obesity and insulin resistance (IR).

Subjects/methods: Here we characterized T and NK cell populations in omental AT (OAT) from women (n = 18) with morbid obesity and varying levels of IR and performed an integrated analysis of metabolic parameters and adipose tissue transcriptomics.

Results: In OAT, we found a distinct population of CD56NKp46EOMES NK cells characterized by expression of cytotoxic molecules, pro-inflammatory cytokines, and markers of cell activation. AT IFNγ NK cells, but not CD4, CD8 or γδ T cells, were positively associated with glucose levels, glycated hemoglobin (HbA1c) and IR. AT NK cells were linked to a pro-inflammatory gene expression profile in AT and developed an effector phenotype in response to IL-12 and IL-15. Moreover, integrated transcriptomic analysis revealed a potential implication of AT IFNγ NK cells in controlling adipose tissue inflammation, remodeling, and lipid metabolism.

Conclusions: Our results suggest that a distinct IFNγ-producing NK cell subset is involved in metabolic homeostasis in visceral AT in humans with obesity and may be a potential target for therapy of IR.
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http://dx.doi.org/10.1038/s41366-021-00826-1DOI Listing
July 2021

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target.

Gut 2021 Apr 26. Epub 2021 Apr 26.

Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France.

Objective: We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans.

Design: Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver.

Results: The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα.

Conclusions: These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.

Trial Registration Number: NCT02390232.
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http://dx.doi.org/10.1136/gutjnl-2020-323323DOI Listing
April 2021

Hypothalamic bile acid-TGR5 signaling protects from obesity.

Cell Metab 2021 Jul 21;33(7):1483-1492.e10. Epub 2021 Apr 21.

University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France.

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity.
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http://dx.doi.org/10.1016/j.cmet.2021.04.009DOI Listing
July 2021

Alterations in Rev-ERBα/BMAL1 ratio and glycated hemoglobin in rotating shift workers: the EuRhythDia study.

Acta Diabetol 2021 Aug 31;58(8):1111-1117. Epub 2021 Mar 31.

Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 100133, Rome, Italy.

Objective: To detect premature gluco-metabolic defects among night shift workers with disturbances in circadian rhythms.

Design And Methods: We performed a hypothesis-generating, cross-sectional analysis of anthropometric, metabolic, lipid, and inflammation parameters, comparing active (a-NSW, n = 111) and former (f-NSW, n = 98) rotating night shift workers with diurnal workers (controls, n = 69). All participants were hospital nurses. We also evaluated the Pittsburgh Sleep Quality Index (PSQI) and assessed expression of transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs), as indicators of the molecular clock.

Results: Both a-NSW and f-NSW participants had significantly higher glycated hemoglobin (HbA1c) and white blood cell counts (WBC) (p < 0.001 for both), PSQI global score (p = 0.001) and diastolic blood pressure levels (p = 0.024) compared with controls. Expression of REV-ERBα/BMAL1 RNA in PBMC was significantly higher in a-NSW (p = 0.05) than in f-NSW or control participants. Multivariate regression analysis showed that working status and PSQI were independent determinants of higher HbA1c levels (p < 0.001).

Conclusions: We demonstrated that young, healthy night shift workers show subclinical abnormalities in HbA1c and changes in peripheral clock gene expression.
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http://dx.doi.org/10.1007/s00592-021-01676-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272695PMC
August 2021

Light therapy improves diurnal blood pressure control in night shift workers via reduction of catecholamines: the EuRhythDia study.

J Hypertens 2021 Aug;39(8):1678-1688

Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: Night shift work is associated with high rates of hypertension and cardiometabolic disease, which are linked to disrupted circadian rhythms. We hypothesized that timed light therapy might improve disrupted circadian rhythms and stabilize diurnal control of blood pressure and glucose in night shift workers.

Methods: We randomized 24 rotating night shift workers (mean age, 36 ± 13 years, 7 men) who had spent a median of 6 years on rotating night shifts (median, six night shifts per month) to 12 weeks of light therapy or no intervention and compared them with 12 daytime workers (37 ± 11 years, 6 men). We measured oral glucose tolerance (OGTT), 24-h blood pressure and arterial stiffness, and the circadian profiles of melatonin, cortisol, metanephrine and nor-metanephrine at baseline, after 12 weeks of intervention, and 12 weeks after the end of intervention.

Results: At baseline, fewer night shift workers showed dipper status as compared with daytime workers (29 vs. 58%; P < 0.001). After 12 weeks of light therapy, there was a highly significant increase in the proportion of dippers (to 58%; P < 0.0001). We also observed a significant decrease in serum glucose during OGTT in the light therapy group (-22%; P < 0.05) with no change in serum insulin. Whilst circadian profiles of melatonin and cortisol were unchanged, plasma metanephrine and nor-metanephrine levels were significantly reduced in the light therapy group (P < 0.01).

Conclusion: Timed light therapy improves diurnal blood pressure control and glucose tolerance in rotating night shift workers. This effect is unrelated to melatonin and cortisol but is paralleled by reduced catecholamine levels.
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http://dx.doi.org/10.1097/HJH.0000000000002848DOI Listing
August 2021

Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19.

Arterioscler Thromb Vasc Biol 2021 05 25;41(5):1760-1773. Epub 2021 Feb 25.

Univ. Lille Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France (A. Dupont, A.R., S. Staessens, M.M., M.R., D.C., E.J., F.L., B.S., F.V., N.R., S. Susen).

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.120.315595DOI Listing
May 2021

NASH-related increases in plasma bile acid levels depend on insulin resistance.

JHEP Rep 2021 Apr 16;3(2):100222. Epub 2020 Dec 16.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Background & Aims: Plasma bile acids (BAs) have been extensively studied as pathophysiological actors in non-alcoholic steatohepatitis (NASH). However, results from clinical studies are often complicated by the association of NASH with type 2 diabetes (T2D), obesity, and insulin resistance (IR). Here, we sought to dissect the relationship between NASH, T2D, and plasma BA levels in a large patient cohort.

Methods: Four groups of patients from the Biological Atlas of Severe Obesity (ABOS) cohort (Clinical Trials number NCT01129297) were included based on the presence or absence of histologically evaluated NASH with or without coincident T2D. Patients were matched for BMI, homeostatic model assessment 2 (HOMA2)-assessed IR, glycated haemoglobin, age, and gender. To study the effect of IR and BMI on the association of plasma BA and NASH, patients from the HEPADIP study were included. In both cohorts, fasting plasma BA concentrations were measured.

Results: Plasma BA concentrations were higher in NASH compared with No-NASH patients both in T2D and NoT2D patients from the ABOS cohort. As we previously reported that plasma BA levels were unaltered in NASH patients of the HEPADIP cohort, we assessed the impact of BMI and IR on the association of NASH and BA on the combined BA datasets. Our results revealed that NASH-associated increases in plasma total cholic acid (CA) concentrations depend on the degree of HOMA2-assessed systemic IR, but not on β-cell function nor on BMI.

Conclusions: Plasma BA concentrations are elevated only in those NASH patients exhibiting pronounced IR.

Lay Summary: Non-alcoholic steatohepatitis (NASH) is a progressive liver disease that frequently occurs in patients with obesity and type 2 diabetes. Reliable markers for the diagnosis of NASH are needed. Plasma bile acids have been proposed as NASH biomarkers. Herein, we found that plasma bile acids are only elevated in patients with NASH when significant insulin resistance is present, limiting their utility as NASH markers.
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http://dx.doi.org/10.1016/j.jhepr.2020.100222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878982PMC
April 2021

Apolipoprotein A5 controls fructose-induced metabolic dysregulation in mice.

Nutr Metab Cardiovasc Dis 2021 03 17;31(3):972-978. Epub 2020 Nov 17.

Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria; Christan Doppler Laboratory for Metabolic Crosstalk, Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background And Aims: Western dietary habits are partially characterized by increased uptake of fructose, which contributes to metabolic dysregulation and associated liver diseases. For example, a diet enriched with fructose drives insulin resistance and non-alcoholic fatty liver disease (NAFLD). The molecular hubs that control fructose-induced metabolic dysregulation are poorly understood. Apolipoprotein A5 (apoA5) controls triglyceride metabolism with a putative role in hepatic lipid deposition. We explored apoA5 as a rheostat for fructose-induced hepatic and metabolic disease in mammals.

Methods And Results: ApoA5 knock out (-/-) and wildtype (wt) mice were fed with high fructose diet or standard diet for 10 weeks. Afterwards, we conducted a metabolic characterization by insulin tolerance test as well as oral glucose tolerance test. Additionally, hepatic lipid content as well as transcription patterns of key enzymes and transcription factors in glucose and lipid metabolism were evaluated. Despite comparable body weight, insulin sensitivity was significantly improved in high fructose diet fed apoA5 (-/-) when compared to wildtype mice on the same diet. In parallel, hepatic triglyceride content was significantly lower in apoA5 (-/-) mice than in wt mice. No difference was seen between apoA5 (-/-) and wt mice on a standard diet.

Conclusion: ApoA5 is involved in fructose-induced metabolic dysregulation and associated hepatic steatosis suggesting that apoA5 may be a novel target to treat metabolic diseases.
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http://dx.doi.org/10.1016/j.numecd.2020.11.008DOI Listing
March 2021

PPARs in liver physiology.

Biochim Biophys Acta Mol Basis Dis 2021 May 29;1867(5):166097. Epub 2021 Jan 29.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France. Electronic address:

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and transcriptional modulators with crucial functions in hepatic and whole-body energy homeostasis. Besides their well-documented roles in lipid and glucose metabolism, emerging evidence also implicate PPARs in the control of other processes such as inflammatory responses. Recent technological advances, such as single-cell RNA sequencing, have allowed to unravel an unexpected complexity in the regulation of PPAR expression, activity and downstream signaling. Here we provide an overview of the latest advances in the study of PPARs in liver physiology, with a specific focus on formerly neglected aspects of PPAR regulation, such as tissular zonation, cellular heterogeneity, circadian rhythms, sexual dimorphism and species-specific features.
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http://dx.doi.org/10.1016/j.bbadis.2021.166097DOI Listing
May 2021

Characterization of one anastomosis gastric bypass and impact of biliary and common limbs on bile acid and postprandial glucose metabolism in a minipig model.

Am J Physiol Endocrinol Metab 2021 04 25;320(4):E772-E783. Epub 2021 Jan 25.

U1190, Institut Pasteur de Lille, University of Lille, Inserm, Lille, France.

The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss. Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.
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http://dx.doi.org/10.1152/ajpendo.00356.2020DOI Listing
April 2021

A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA.

J Hepatol 2021 Jun 21;74(6):1344-1354. Epub 2021 Jan 21.

Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University Health System, Richmond, Virginia, USA.

Background & Aims: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC.

Methods: This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108).

Results: At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p <0.001 vs. placebo) and by -40.6±17.4% in the elafibranor 120 mg group (p <0.001) compared to a +3.2±14.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5'-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate.

Conclusion: In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid.

Lay Summary: Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy.

Clinical Trial Registration Number: Clinical Trials.gov NCT03124108.
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http://dx.doi.org/10.1016/j.jhep.2021.01.013DOI Listing
June 2021

Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure-Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor.

J Med Chem 2021 02 20;64(3):1593-1610. Epub 2021 Jan 20.

Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000 Lille, France.

PEGylation of therapeutic agents is known to improve the pharmacokinetic behavior of macromolecular drugs and nanoparticles. In this work, we performed the conjugation of polyethylene glycols (220-5000 Da) to a series of non-steroidal small agonists of the bile acids receptor TGR5. A suitable anchoring position on the agonist was identified to retain full agonistic potency with the conjugates. We describe herein an extensive structure-properties relationships study allowing us to finely describe the non-linear effects of the PEG length on the physicochemical as well as the and pharmacokinetic properties of these compounds. When appending a PEG of suitable length to the TGR5 pharmacophore, we were able to identify either systemic or gut lumen-restricted TGR5 agonists.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01774DOI Listing
February 2021

Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid.

Cell Mol Gastroenterol Hepatol 2021 10;11(4):1045-1069. Epub 2020 Dec 10.

Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background And Aims: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice.

Methods: The consequences of Cyp2c70-deficiency were assessed in male and female mice at different ages.

Results: Cyp2c70 mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70-deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70 mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70-deficiency differed considerably between sexes. Three-week old male Cyp2c70 mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70 mice up to 8 months of age. In female Cyp2c70 mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70 mice.

Conclusion: Cyp2c70 mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70-deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development.
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http://dx.doi.org/10.1016/j.jcmgh.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898074PMC
December 2020

Saturated Fatty Acids Promote GDF15 Expression in Human Macrophages through the PERK/eIF2/CHOP Signaling Pathway.

Nutrients 2020 Dec 8;12(12). Epub 2020 Dec 8.

Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France.

Growth differentiation factor-15 (GDF-15) and its receptor GFRAL are both involved in the development of obesity and insulin resistance. Plasmatic GDF-15 level increases with obesity and is positively associated with disease progression. Despite macrophages have been recently suggested as a key source of GDF-15 in obesity, little is known about the regulation of GDF-15 in these cells. In the present work, we sought for potential pathophysiological activators of expression in human macrophages and identified saturated fatty acids (SFAs) as strong inducers of expression and secretion. SFAs increase expression through the induction of an ER stress and the activation of the PERK/eIF2/CHOP signaling pathway in both PMA-differentiated THP-1 cells and in primary monocyte-derived macrophages. The transcription factor CHOP directly binds to the promoter region and regulates expression. Unlike SFAs, unsaturated fatty acids do not promote expression and rather inhibit both SFA-induced expression and ER stress. These results suggest that free fatty acids may be involved in the control of GDF-15 and provide new molecular insights about how diet and lipid metabolism may regulate the development of obesity and T2D.
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http://dx.doi.org/10.3390/nu12123771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764024PMC
December 2020

Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis.

Int J Mol Sci 2020 Dec 7;21(23). Epub 2020 Dec 7.

Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium.

Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it has been reported that PPARγ expression is decreased in peripheral blood mononuclear cells of MS patients. The goal of the present study was to determine to what extent , as well as the closely related nuclear receptors and and and , are differentially expressed in monocytes from MS patients and how this change in expression affects the function of monocyte-derived macrophages. We demonstrate that monocytes of relapsing-remitting MS patients display a marked decrease in expression, while the expression of and is not altered. Interestingly, exposure of monocyte-derived macrophages from healthy donors to MS-associated proinflammatory cytokines mimicked this reduction in expression. While a reduced expression did not affect the inflammatory and phagocytic properties of myelin-loaded macrophages, it did impact myelin processing by increasing the intracellular cholesterol load of myelin-phagocytosing macrophages. Collectively, our findings indicate that an inflammation-induced reduction in expression promotes myelin-induced foam cell formation in macrophages in MS.
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http://dx.doi.org/10.3390/ijms21239329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731422PMC
December 2020

Deletion of the nuclear receptor RORα in macrophages does not modify the development of obesity, insulin resistance and NASH.

Sci Rep 2020 12 3;10(1):21095. Epub 2020 Dec 3.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000, Lille, France.

Retinoic acid receptor-related orphan receptor-alpha (RORα) is a transcription factor from the nuclear receptor family expressed by immune cells and involved in the development of obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). It was recently reported that mice deficient for RORα in macrophages develop more severe NASH upon high fat diet (HFD) feeding due to altered Kupffer cell function. To better understand the role of RORα in obesity and IR, we independently generated a macrophage RORα-deficient mouse line. We report that RORα deletion in macrophages does not impact on HFD-induced obesity and IR. Surprisingly, we did not confirm an effect on NASH development upon HFD feeding nor in the more severe and obesity-independent choline-deficient, L-amino acid-defined diet model. Our results therefore show that RORα deletion in macrophages does not alter the development of obesity and IR and question its role in NASH.
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http://dx.doi.org/10.1038/s41598-020-77858-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713245PMC
December 2020

GIANT: galaxy-based tool for interactive analysis of transcriptomic data.

Sci Rep 2020 11 16;10(1):19835. Epub 2020 Nov 16.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000, Lille, France.

Transcriptomic analyses are broadly used in biomedical research calling for tools allowing biologists to be directly involved in data mining and interpretation. We present here GIANT, a Galaxy-based tool for Interactive ANalysis of Transcriptomic data, which consists of biologist-friendly tools dedicated to analyses of transcriptomic data from microarray or RNA-seq analyses. GIANT is organized into modules allowing researchers to tailor their analyses by choosing the specific set of tool(s) to analyse any type of preprocessed transcriptomic data. It also includes a series of tools dedicated to the handling of raw Affymetrix microarray data. GIANT brings easy-to-use solutions to biologists for transcriptomic data mining and interpretation.
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http://dx.doi.org/10.1038/s41598-020-76769-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670435PMC
November 2020

Human Aortic Valve Interstitial Cells Display Proangiogenic Properties During Calcific Aortic Valve Disease.

Arterioscler Thromb Vasc Biol 2021 01 5;41(1):415-429. Epub 2020 Nov 5.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, France (N.G., A.B., E.R., S.I., S.L., A. Cras, N.N., J.R., P.G., D.M.S.).

Objective: The study's aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VIC) mesenchymal-like phenotype was confirmed by CD90/CD73/CD44 expression and multipotent-like differentiation ability. When VIC were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VIC and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VIC-conditioned media and confirmed at the mRNA level in VIC compared with control VIC. Conditioned media from VIC induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VIC involvement in angiogenesis by a VEGF-A dependent mechanism.

Conclusions: We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VIC in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.
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http://dx.doi.org/10.1161/ATVBAHA.120.314287DOI Listing
January 2021

CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway.

J Biol Chem 2020 12 9;295(50):17310-17322. Epub 2020 Oct 9.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France. Electronic address:

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near , the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of and approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, overexpression was associated with triglyceride accumulation and increased lipid droplet numbers , and decreased ketogenesis and hepatic mitochondrial activity Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between expression and and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.
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http://dx.doi.org/10.1074/jbc.RA120.012543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863903PMC
December 2020

Dysregulated lipid metabolism links NAFLD to cardiovascular disease.

Mol Metab 2020 12 1;42:101092. Epub 2020 Oct 1.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients.

Scope Of Review: In this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk.

Major Conclusions: Alterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.
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http://dx.doi.org/10.1016/j.molmet.2020.101092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600388PMC
December 2020

Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology.

Cells 2020 09 28;9(10). Epub 2020 Sep 28.

Institut Pasteur de Lille, The University of Lille, Inserm, CHU Lille, U1011-EGID, F-59000 Lille, France.

Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor family whose expression and activities are restricted to a limited number of organs including the liver and gastrointestinal tract. In this review, we present robust evidence pointing to HNF4 as a master regulator of cellular differentiation during development and a safekeeper of acquired cell identity in adult organs. Importantly, we discuss that transient loss of HNF4 may represent a protective mechanism upon acute organ injury, while prolonged impairment of HNF4 activities could contribute to organ dysfunction. In this context, we describe in detail mechanisms involved in the pathophysiological control of cell identity by HNF4, including how HNF4 works as part of cell-specific TF networks and how its expression/activities are disrupted in injured organs.
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http://dx.doi.org/10.3390/cells9102185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600215PMC
September 2020

Timed physical exercise does not influence circadian rhythms and glucose tolerance in rotating night shift workers: The EuRhythDia study.

Diab Vasc Dis Res 2020 May-Jun;17(5):1479164120950616

Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: Night shift workers are at cardiometabolic risk due to circadian misalignment. We investigated whether infrequent exercise before each night shift that intentionally would not improve physical performance improves glucose tolerance and 24-h blood pressure profiles and synchronizes circadian rhythms of melatonin and cortisol in rotating night shift workers.

Methods: A total of 24 rotating night shift workers (mean age, 35.7 ± 11.8 years) were randomized to exercise or no intervention. Workers in the exercise group performed 15.2 ± 4.5 exercise sessions within 2 h before each night shift. Before and after 12 weeks of exercise intervention and 12 weeks after the intervention, spiroergometry, oral glucose tolerance testing and 24-h blood pressure profiles were performed. Plasma melatonin and cortisol levels were measured in 3-hourly intervals during one 24-h period on each study day.

Results: Exercise did not significantly change serum glucose nor insulin levels during oral glucose tolerance testing. Timed physical exercise had no effect on physical performance, nor did it change the circadian rhythms of melatonin and cortisol or influence 24-h blood pressure profiles.

Conclusion: Physical exercise before each night shift at a low intensity level that does not improve physical performance does not affect circadian timing, glucose tolerance or 24-h blood pressure profiles in rotating night shift workers.
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http://dx.doi.org/10.1177/1479164120950616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919228PMC
January 2021

A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study.

Lancet Gastroenterol Hepatol 2020 11 5;5(11):970-985. Epub 2020 Aug 5.

Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

Background: Non-invasive tests that can identify patients with non-alcoholic steatohepatitis (NASH) at higher risk of disease progression are lacking. We report the development and validation of a blood-based diagnostic test to non-invasively rule in and rule out at-risk NASH (defined as non-alcoholic fatty liver disease [NAFLD] activity score [NAS] ≥4 and fibrosis stage ≥2).

Methods: In this prospective derivation and global validation study, blood samples, clinical data, and liver biopsy results from three independent cohorts with suspected NAFLD were used to develop and validate a non-invasive blood-based diagnostic test, called NIS4. Derivation was done in the discovery cohort, which comprised 239 prospectively recruited patients with biopsy-confirmed NASH (NAFLD NAS ≥3; fibrosis stage 0-3) from the international GOLDEN-505 phase 2b clinical trial. A complete matrix based on 23 variables selected for univariate association with the presence of at-risk NASH and avoiding high multi-collinearity was used to derive the model in a bootstrap-based process that minimised the Akaike information criterion. The overall diagnostic performance of NIS4 was externally validated in two independent cohorts: RESOLVE-IT diag and Angers. The RESOLVE-IT diag cohort comprised the first 475 patients screened for potential inclusion into the RESOLVE-IT phase 3 clinical trial. Angers was a retrospective cohort of 227 prospectively recruited patients with suspected NAFLD and clinical risk factors for NASH or fibrosis stage 2 or more according to abnormal elastography results or abnormal liver biochemistry. Both external validation cohorts were independently analysed and were combined into a pooled validation cohort (n=702) to assess clinical performance of NIS4 and other non-invasive tests.

Findings: The derived NIS4 algorithm comprised four independent NASH-associated biomarkers (miR-34a-5p, alpha-2 macroglobulin, YKL-40, and glycated haemoglobin; area under the receiver operating characteristics curve [AUROC] 0·80, 95% CI 0·73-0·85), and did not require adjustment for age, sex, body-mass index (BMI), or aminotransferase concentrations. Clinical cutoffs were established within the discovery cohort to optimise both rule out and rule in clinical performance while minimising indeterminate results. NIS4 was validated in the RESOLVE-IT diag cohort (AUROC 0·83, 95% CI 0·79-0·86) and the Angers cohort (0·76, 0·69-0·82). In the pooled validation cohort, patients with a NIS4 value less than 0·36 were classified as not having at-risk NASH (ruled out) with 81·5% (95% CI 76·9-85·3) sensitivity, 63·0% (57·8-68·0) specificity, and a negative predictive value of 77·9% (72·5-82·4), whereas those with a NIS4 value of more than 0·63 were classified as having at-risk NASH (ruled in) with 87·1% (83·1-90·3) specificity, 50·7% (45·3-56·1) sensitivity, and a positive predictive value of 79·2% (73·1-84·2). The diagnostic performance of NIS4 within the external validation cohorts was not influenced by age, sex, BMI, or aminotransferase concentrations.

Interpretation: NIS4 is a novel blood-based diagnostic that provides an effective way to non-invasively rule in or rule out at-risk NASH in patients with metabolic risk factors and suspected disease. Use of NIS4 in clinical trials or in the clinic has the potential to greatly reduce unnecessary liver biopsies in patients with lower risk of disease progression.

Funding: Genfit.
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http://dx.doi.org/10.1016/S2468-1253(20)30252-1DOI Listing
November 2020
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