Sven Francque - Academia.edu (original) (raw)

Papers by Sven Francque

Research paper thumbnail of Additional file 2 of A targeted multi-omics approach reveals paraoxonase-1 as a determinant of obesity-associated fatty liver disease

Additional file 2. Supplementary statistics table.

Research paper thumbnail of Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome

Circulation Research, 2022

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of ... more Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. ...

Research paper thumbnail of Top level research in hepatology: COVID-19 and beyond

JHEP Reports, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Reply: To PMID 24375485

Hepatology, 2014

ing to Hp-related CVD risk; Hp-I is associated with increased tumor necrosis factor alpha (TNF-a)... more ing to Hp-related CVD risk; Hp-I is associated with increased tumor necrosis factor alpha (TNF-a), a circulating cytokine able to exert its effects at a distance. TNF-a and interleukin (IL)26 (TNF-a is the main trigger for the production of IL-6 by a variety of cells) play important roles in the regulation of synthesis of other acute phase proteins, which are established risk factors for atherosclerosis, such as the mentioned fibrinogen and factor VIII; and circulating lipid peroxides, also associated with cardiovascular risk, are raised in Hp-positive patients. Therefore, Hp eradication might display a positive effect on Hprelated NAFLD and CVD development/progression by inhibiting various prothrombotic and proinflammatory agents partly in some Hp-positive ethnic subpopulations. Because there is a lack of literature showing any demonstrable evidence to support the aforementioned hypothesis, large-scale studies are warranted to elucidate our hypothesis.

Research paper thumbnail of Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease

Gut, 2021

ObjectiveLiver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and ... more ObjectiveLiver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.DesignThis international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.ResultsAfter screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (...

Research paper thumbnail of Muscle fat content is strongly associated with NASH: A longitudinal study in patients with morbid obesity

Journal of Hepatology, 2021

Normal NAFL NASH Diet or bariatric surgery Increased muscle mass Increased fat content Non-invasi... more Normal NAFL NASH Diet or bariatric surgery Increased muscle mass Increased fat content Non-invasive CT-scan At inclusion: Morbidly obese n = 184 Liver biopsy 1-year follow-up n = 39 Normal/NAFL Highlights Muscle fat content is higher in patients with obesity and NASH than in those with obesity and NAFL. There is no low muscle mass in patients with obesity-associated NASH.

Research paper thumbnail of A transcriptomic signature predicting fibrosis progression in a large European cohort of patients with histologically characterised NAFLD

Journal of Hepatology, 2020

Research paper thumbnail of Unlike HbA1c level and the amount of visceral adipose tissue, the presence and severity of NAFLD do not predict the occurrence of major adverse cardiovascular events in an obese Belgian population

Journal of Hepatology, 2020

Research paper thumbnail of Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH)

Hepatology, 2020

Background and Aims: Non-Alcoholic SteatoHepatitis (NASH) is considered as a pivotal stage in Non... more Background and Aims: Non-Alcoholic SteatoHepatitis (NASH) is considered as a pivotal stage in Non-Alcoholic Fatty Liver Disease (NAFLD) progression, as it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multifactorial and identifying reliable molecular players and/or biomarkers has proven difficult. Together with the inappropriate consideration of risk factors revealed by epidemiological studies (altered glucose homeostasis, obesity, ethnicity, sex…), the limited availability of representative NASH cohorts with associated liver biopsies, the gold standard for NASH diagnosis, probably explains the poor overlap between published "omics"-defined NASH signatures. Approach & Results: Here we have explored transcriptomic profiles of livers starting from a 910 obese patient cohort which was further stratified based on stringent histological characterization, to define "NoNASH" and "NASH" patients. Sex was identified as the main factor for data heterogeneity in this cohort. Using powerful bootstrapping and random forest (RF) approaches, we identified reliably differentially expressed genes participating to distinct biological processes in NASH as a function of sex. RF-calculated gene signatures identified NASH patients in independent cohorts with high accuracy. Conclusions: This largescale analysis of transcriptomic profiles from human livers emphasized the sexually dimorphic nature of NASH and its link with fibrosis, calling for the integration of sex as a major determinant of liver responses to NASH progression and responses to drugs.

Research paper thumbnail of Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆

Journal of Hepatology, 2020

Genome-wide association study involved 1,483 biopsied NAFLD cases and 17,781 controls. Main analy... more Genome-wide association study involved 1,483 biopsied NAFLD cases and 17,781 controls. Main analysis shows genome-wide significance for PNPLA3, TM6SF2, HSD17B13 and GCKR. Sub-analyses show significance near LEPR for NASH and near PYGO1 for steatosis. Except for GCKR, the genome-wide significant signals were replicated.

Research paper thumbnail of The current issue of JHEP Reports

Research paper thumbnail of Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution

Nature Metabolism, 2019

Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health pr... more Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. Presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of NASH patients before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed NAFLD reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity upon LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intrahepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.

Research paper thumbnail of Portal Hypertension in NASH: Is It Different from Other Aetiologies?

Current Hepatology Reports, 2019

Purpose of review: In non-alcoholic fatty liver disease (NAFLD), an increased portal pressure is ... more Purpose of review: In non-alcoholic fatty liver disease (NAFLD), an increased portal pressure is observed before cirrhosis or even inflammation or fibrosis are histologically present. This review describes the differences between the mechanisms of cirrhotic portal hypertension (PHT) and PHT in non-cirrhotic NAFLD. Recent findings: The increased portal pressure in NAFLD is primarily a result of an increased intrahepatic vascular resistance. Vasodilation is decreased by endothelial dysfunction and the sensitivity to vasoconstrictors is increased. Furthermore, the activation of hepatic stellate cells and the presence of microvascular thrombosis could also be involved in the pathogenesis of PHT in NAFLD. Summary: Although the increased portal pressure in early NAFLD is not considered clinically significant PHT, it might play a role in the pathophysiology of NAFLD. Due to the increased intrahepatic vascular resistance, the hepatic blood flow is impaired and hence the oxygen delivery is decreased, potentially triggering transition to steatohepatitis. The underlying mechanisms of these alterations therefore represent promising targets for pharmacological treatment.

Research paper thumbnail of Targeting Myeloid-Derived Cells: New Frontiers in the Treatment of Non-alcoholic and Alcoholic Liver Disease

Frontiers in Immunology, 2019

Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of l... more Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of liver-related morbidity and mortality and constitute important causes of liver transplantation. The spectrum of the liver disease is wide and includes isolated steatosis, steatohepatitis, and cirrhosis. The treatment of NAFLD and ALD remains, however, an unmet need, and therefore it is a public health priority to develop effective treatments for these diseases. Alcoholic and non-alcoholic liver disease share common complex pathogenetic pathways that involve different organs and systems beyond the liver, including the gut, the adipose tissue, and the immune system, which cross-talk to generate damage. Myeloid-derived cells have been widely studied in the setting of NAFLD and ALD and are implicated at different levels in the onset and progression of this disease. Among these cells, monocytes and macrophages have been found to be involved in the induction of inflammation and in the progression to fibrosis, both in animal models and clinical studies and they have become interesting potential targets for the treatment of both NAFLD and ALD. The different mechanisms by which these cells can be targeted include modulation of Kupffer cell activation, monocyte recruitment in the liver and macrophage polarization and differentiation. Evidence from preclinical studies and clinical trials (some of them already in phase II and III) have shown encouraging results in ameliorating steatohepatitis, fibrosis, and the metabolic profile, individuating promising candidates for the pharmacological treatment of these diseases. The currently available results of myeloid-derived cells targeted treatments in NAFLD and ALD are covered in this review.

Research paper thumbnail of The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis

Research paper thumbnail of Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats

Laboratory Investigation, 2018

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. Th... more Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-cholinedeficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.

Research paper thumbnail of The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Hepatology Communications, 2017

IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-... more IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (a, c, d). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet-induced obesity model (high-fat/high-sucrose diet); a methionine-and choline-deficient diet; the foz/foz model; the CCl 4-induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl 4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of b-oxidation-related and fatty acid desaturation-related genes in both the methionineand choline-deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARa, PPARd, or PPARc agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data.

Research paper thumbnail of The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C infected patients treated with direct acting antivirals with and without pegylated interferon: a Belgian experience

Journal of Hepatology, 2017

The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C infected p... more The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C infected patients treated w ith direct acting antivirals w ith and w ithout Pegylated Interferon : a Belgian experience

Research paper thumbnail of Assessment of biopsy‐proven liver fibrosis by two‐dimensional shear wave elastography: An individual patient data‐based meta‐analysis

Hepatology, 2017

Two-dimensional shear wave elastography (2D-SWE) has proven to be efficient for the evaluation of... more Two-dimensional shear wave elastography (2D-SWE) has proven to be efficient for the evaluation of liver fibrosis in small to moderate-sized clinical trials. We aimed at running a larger-scale meta-analysis of individual data. Centers which have worked with Aixplorer ultrasound equipment were contacted to share their data. Retrospective statistical analysis used direct and paired receiver operating characteristic and area under the receiver operating characteristic curve (AUROC) analyses, accounting for random effects. Data on both 2D-SWE and liver biopsy were available for 1,134 patients from 13 sites, as well as on successful transient elastography in 665 patients. Most patients had chronic hepatitis C (n 5 379), hepatitis B (n 5 400), or nonalcoholic fatty liver disease (n 5 156). AUROCs of 2D-SWE in patients with hepatitis C, hepatitis B, and nonalcoholic fatty liver disease were 86.3%, 90.6%, and 85.5% for diagnosing significant fibrosis and 92.9%, 95.5%, and 91.7% for diagnosing cirrhosis, respectively. The AUROC of 2D-SWE was 0.022-0.084 (95% confidence interval) larger than the AUROC of transient elastography for diagnosing significant fibrosis (P 5 0.001) and 0.003-0.034 for diagnosing cirrhosis (P 5 0.022) in all patients. This difference was strongest in hepatitis B patients. Conclusion: 2D-SWE has good to excellent performance for the noninvasive staging of liver fibrosis in patients with hepatitis B; further prospective studies are needed for head-to-head comparison between 2D-SWE and other imaging modalities to establish diseasespecific appropriate cutoff points for assessment of fibrosis stage.

Research paper thumbnail of A stepwise algorithm using a at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis

Journal of hepatology, Jan 11, 2017

Chronic liver diseases (CLD) are highly frequent and thus mainly managed by non-hepatologists. Be... more Chronic liver diseases (CLD) are highly frequent and thus mainly managed by non-hepatologists. Because they lack access to the best non-invasive tests of liver fibrosis, these physicians cannot accurately determine the disease severity and the need for referral to a hepatologist. We aimed to implement an algorithm, comprising a new first-line test usable by all physicians, for the detection of advanced liver fibrosis in all CLD patients. Diagnostic study: 3,754 CLD patients with liver biopsy were 2:1 randomized into derivation and validation sets. Prognostic study: longitudinal follow-up of 1,275 CLD patients with baseline fibrosis tests. Diagnostic study: the easy LIver Fibrosis Test (eLIFT), an "at-a-glance" sum of points attributed to age, gender, gamma-GT, AST, platelets and prothrombin time, was developed for the diagnosis of advanced fibrosis. In the validation set, eLIFT and FIB4 had the same sensitivity (78.0% vs 76.6%, p=0.470) but eLIFT gave less false-positive r...

Research paper thumbnail of Additional file 2 of A targeted multi-omics approach reveals paraoxonase-1 as a determinant of obesity-associated fatty liver disease

Additional file 2. Supplementary statistics table.

Research paper thumbnail of Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome

Circulation Research, 2022

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of ... more Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. ...

Research paper thumbnail of Top level research in hepatology: COVID-19 and beyond

JHEP Reports, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Reply: To PMID 24375485

Hepatology, 2014

ing to Hp-related CVD risk; Hp-I is associated with increased tumor necrosis factor alpha (TNF-a)... more ing to Hp-related CVD risk; Hp-I is associated with increased tumor necrosis factor alpha (TNF-a), a circulating cytokine able to exert its effects at a distance. TNF-a and interleukin (IL)26 (TNF-a is the main trigger for the production of IL-6 by a variety of cells) play important roles in the regulation of synthesis of other acute phase proteins, which are established risk factors for atherosclerosis, such as the mentioned fibrinogen and factor VIII; and circulating lipid peroxides, also associated with cardiovascular risk, are raised in Hp-positive patients. Therefore, Hp eradication might display a positive effect on Hprelated NAFLD and CVD development/progression by inhibiting various prothrombotic and proinflammatory agents partly in some Hp-positive ethnic subpopulations. Because there is a lack of literature showing any demonstrable evidence to support the aforementioned hypothesis, large-scale studies are warranted to elucidate our hypothesis.

Research paper thumbnail of Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease

Gut, 2021

ObjectiveLiver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and ... more ObjectiveLiver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.DesignThis international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.ResultsAfter screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (...

Research paper thumbnail of Muscle fat content is strongly associated with NASH: A longitudinal study in patients with morbid obesity

Journal of Hepatology, 2021

Normal NAFL NASH Diet or bariatric surgery Increased muscle mass Increased fat content Non-invasi... more Normal NAFL NASH Diet or bariatric surgery Increased muscle mass Increased fat content Non-invasive CT-scan At inclusion: Morbidly obese n = 184 Liver biopsy 1-year follow-up n = 39 Normal/NAFL Highlights Muscle fat content is higher in patients with obesity and NASH than in those with obesity and NAFL. There is no low muscle mass in patients with obesity-associated NASH.

Research paper thumbnail of A transcriptomic signature predicting fibrosis progression in a large European cohort of patients with histologically characterised NAFLD

Journal of Hepatology, 2020

Research paper thumbnail of Unlike HbA1c level and the amount of visceral adipose tissue, the presence and severity of NAFLD do not predict the occurrence of major adverse cardiovascular events in an obese Belgian population

Journal of Hepatology, 2020

Research paper thumbnail of Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH)

Hepatology, 2020

Background and Aims: Non-Alcoholic SteatoHepatitis (NASH) is considered as a pivotal stage in Non... more Background and Aims: Non-Alcoholic SteatoHepatitis (NASH) is considered as a pivotal stage in Non-Alcoholic Fatty Liver Disease (NAFLD) progression, as it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multifactorial and identifying reliable molecular players and/or biomarkers has proven difficult. Together with the inappropriate consideration of risk factors revealed by epidemiological studies (altered glucose homeostasis, obesity, ethnicity, sex…), the limited availability of representative NASH cohorts with associated liver biopsies, the gold standard for NASH diagnosis, probably explains the poor overlap between published "omics"-defined NASH signatures. Approach & Results: Here we have explored transcriptomic profiles of livers starting from a 910 obese patient cohort which was further stratified based on stringent histological characterization, to define "NoNASH" and "NASH" patients. Sex was identified as the main factor for data heterogeneity in this cohort. Using powerful bootstrapping and random forest (RF) approaches, we identified reliably differentially expressed genes participating to distinct biological processes in NASH as a function of sex. RF-calculated gene signatures identified NASH patients in independent cohorts with high accuracy. Conclusions: This largescale analysis of transcriptomic profiles from human livers emphasized the sexually dimorphic nature of NASH and its link with fibrosis, calling for the integration of sex as a major determinant of liver responses to NASH progression and responses to drugs.

Research paper thumbnail of Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆

Journal of Hepatology, 2020

Genome-wide association study involved 1,483 biopsied NAFLD cases and 17,781 controls. Main analy... more Genome-wide association study involved 1,483 biopsied NAFLD cases and 17,781 controls. Main analysis shows genome-wide significance for PNPLA3, TM6SF2, HSD17B13 and GCKR. Sub-analyses show significance near LEPR for NASH and near PYGO1 for steatosis. Except for GCKR, the genome-wide significant signals were replicated.

Research paper thumbnail of The current issue of JHEP Reports

Research paper thumbnail of Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution

Nature Metabolism, 2019

Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health pr... more Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. Presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of NASH patients before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed NAFLD reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity upon LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intrahepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.

Research paper thumbnail of Portal Hypertension in NASH: Is It Different from Other Aetiologies?

Current Hepatology Reports, 2019

Purpose of review: In non-alcoholic fatty liver disease (NAFLD), an increased portal pressure is ... more Purpose of review: In non-alcoholic fatty liver disease (NAFLD), an increased portal pressure is observed before cirrhosis or even inflammation or fibrosis are histologically present. This review describes the differences between the mechanisms of cirrhotic portal hypertension (PHT) and PHT in non-cirrhotic NAFLD. Recent findings: The increased portal pressure in NAFLD is primarily a result of an increased intrahepatic vascular resistance. Vasodilation is decreased by endothelial dysfunction and the sensitivity to vasoconstrictors is increased. Furthermore, the activation of hepatic stellate cells and the presence of microvascular thrombosis could also be involved in the pathogenesis of PHT in NAFLD. Summary: Although the increased portal pressure in early NAFLD is not considered clinically significant PHT, it might play a role in the pathophysiology of NAFLD. Due to the increased intrahepatic vascular resistance, the hepatic blood flow is impaired and hence the oxygen delivery is decreased, potentially triggering transition to steatohepatitis. The underlying mechanisms of these alterations therefore represent promising targets for pharmacological treatment.

Research paper thumbnail of Targeting Myeloid-Derived Cells: New Frontiers in the Treatment of Non-alcoholic and Alcoholic Liver Disease

Frontiers in Immunology, 2019

Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of l... more Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of liver-related morbidity and mortality and constitute important causes of liver transplantation. The spectrum of the liver disease is wide and includes isolated steatosis, steatohepatitis, and cirrhosis. The treatment of NAFLD and ALD remains, however, an unmet need, and therefore it is a public health priority to develop effective treatments for these diseases. Alcoholic and non-alcoholic liver disease share common complex pathogenetic pathways that involve different organs and systems beyond the liver, including the gut, the adipose tissue, and the immune system, which cross-talk to generate damage. Myeloid-derived cells have been widely studied in the setting of NAFLD and ALD and are implicated at different levels in the onset and progression of this disease. Among these cells, monocytes and macrophages have been found to be involved in the induction of inflammation and in the progression to fibrosis, both in animal models and clinical studies and they have become interesting potential targets for the treatment of both NAFLD and ALD. The different mechanisms by which these cells can be targeted include modulation of Kupffer cell activation, monocyte recruitment in the liver and macrophage polarization and differentiation. Evidence from preclinical studies and clinical trials (some of them already in phase II and III) have shown encouraging results in ameliorating steatohepatitis, fibrosis, and the metabolic profile, individuating promising candidates for the pharmacological treatment of these diseases. The currently available results of myeloid-derived cells targeted treatments in NAFLD and ALD are covered in this review.

Research paper thumbnail of The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis

Research paper thumbnail of Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats

Laboratory Investigation, 2018

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. Th... more Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-cholinedeficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.

Research paper thumbnail of The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Hepatology Communications, 2017

IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-... more IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (a, c, d). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet-induced obesity model (high-fat/high-sucrose diet); a methionine-and choline-deficient diet; the foz/foz model; the CCl 4-induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl 4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of b-oxidation-related and fatty acid desaturation-related genes in both the methionineand choline-deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARa, PPARd, or PPARc agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data.

Research paper thumbnail of The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C infected patients treated with direct acting antivirals with and without pegylated interferon: a Belgian experience

Journal of Hepatology, 2017

The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C infected p... more The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C infected patients treated w ith direct acting antivirals w ith and w ithout Pegylated Interferon : a Belgian experience

Research paper thumbnail of Assessment of biopsy‐proven liver fibrosis by two‐dimensional shear wave elastography: An individual patient data‐based meta‐analysis

Hepatology, 2017

Two-dimensional shear wave elastography (2D-SWE) has proven to be efficient for the evaluation of... more Two-dimensional shear wave elastography (2D-SWE) has proven to be efficient for the evaluation of liver fibrosis in small to moderate-sized clinical trials. We aimed at running a larger-scale meta-analysis of individual data. Centers which have worked with Aixplorer ultrasound equipment were contacted to share their data. Retrospective statistical analysis used direct and paired receiver operating characteristic and area under the receiver operating characteristic curve (AUROC) analyses, accounting for random effects. Data on both 2D-SWE and liver biopsy were available for 1,134 patients from 13 sites, as well as on successful transient elastography in 665 patients. Most patients had chronic hepatitis C (n 5 379), hepatitis B (n 5 400), or nonalcoholic fatty liver disease (n 5 156). AUROCs of 2D-SWE in patients with hepatitis C, hepatitis B, and nonalcoholic fatty liver disease were 86.3%, 90.6%, and 85.5% for diagnosing significant fibrosis and 92.9%, 95.5%, and 91.7% for diagnosing cirrhosis, respectively. The AUROC of 2D-SWE was 0.022-0.084 (95% confidence interval) larger than the AUROC of transient elastography for diagnosing significant fibrosis (P 5 0.001) and 0.003-0.034 for diagnosing cirrhosis (P 5 0.022) in all patients. This difference was strongest in hepatitis B patients. Conclusion: 2D-SWE has good to excellent performance for the noninvasive staging of liver fibrosis in patients with hepatitis B; further prospective studies are needed for head-to-head comparison between 2D-SWE and other imaging modalities to establish diseasespecific appropriate cutoff points for assessment of fibrosis stage.

Research paper thumbnail of A stepwise algorithm using a at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis

Journal of hepatology, Jan 11, 2017

Chronic liver diseases (CLD) are highly frequent and thus mainly managed by non-hepatologists. Be... more Chronic liver diseases (CLD) are highly frequent and thus mainly managed by non-hepatologists. Because they lack access to the best non-invasive tests of liver fibrosis, these physicians cannot accurately determine the disease severity and the need for referral to a hepatologist. We aimed to implement an algorithm, comprising a new first-line test usable by all physicians, for the detection of advanced liver fibrosis in all CLD patients. Diagnostic study: 3,754 CLD patients with liver biopsy were 2:1 randomized into derivation and validation sets. Prognostic study: longitudinal follow-up of 1,275 CLD patients with baseline fibrosis tests. Diagnostic study: the easy LIver Fibrosis Test (eLIFT), an "at-a-glance" sum of points attributed to age, gender, gamma-GT, AST, platelets and prothrombin time, was developed for the diagnosis of advanced fibrosis. In the validation set, eLIFT and FIB4 had the same sensitivity (78.0% vs 76.6%, p=0.470) but eLIFT gave less false-positive r...