A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis

Hammoutène, Adel; Biquard, Louise; Lasselin, Juliette; Kheloufi, Marouane; Tanguy, Marion; Vion, Anne-Clémence; Mérian, Jules; Colnot, Nathalie; Loyer, Xavier; Tedgui, Alain; Codogno, Patrice; Lotersztajn, Sophie; Paradis, Valérie; Boulanger, Chantal M.; Rautou, Pierre‐Emmanuel

doi:10.1016/j.jhep.2019.10.028

Cited by 129 publications

(117 citation statements)

References 58 publications

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“…These are key proteins for autophagic vesicle formation and lysosome maturation, and their deficit was found to suppress autophagic flux and to impair the autophagosome-lysosome fusion (Xu et al, 2013b). Moreover, autophagy could exert an anti-fibrogenic role since it promotes survival of hepatocytes and hepatocyte apoptosis is a central event in the fibrogenic process (Ni et al, 2014;Ruart et al, 2019;Hammoutene et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is associated with aging and features of metabolic syndrome. Lipotoxicity and oxidative stress are consequent to dysregulation of lipid metabolism and lipid accumulation, leading to hepatocyte injury and inflammation. Lipophagy consists in selective degradation of intracellular lipid droplets by lysosome and mounting evidence suggests that lipophagy is dysregulated in NAFLD. Here we demonstrate lipophagy impairment in experimental models of NAFLD and in a NAFLD patient cohort by histomorphological and molecular analysis. High fat diet-fed C57BL/6J male mice and high-fat/high-glucose cultured Huh7 cells showed accumulation of both p62/SQSTM1 and LC3-II protein. In 59 NAFLD patients, lipid droplet-loaded lysosomes/lipolysosomes and p62/SQSTM1 clusters correlated with NAFLD activity score (NAS) and with NAS and fibrosis stage, respectively, and levels of expression of lysosomal genes, as well as autophagy-related genes, correlated with NAS and fibrosis stage. An increased amount of lipid droplets, lipolysosomes and autophagosomes was found in subjects with NAFLD compared to healthy subjects at ultrastructural level. In conclusion, here we observed that NAFLD is characterized by histological, ultrastructural and molecular features of altered autophagy that is associated with an impaired lipid degradation. Impaired autophagy is associated with features of advanced disease. Lipopolysosomes, as individuated with light microscopy, should be further assessed as markers of disease severity in NAFLD patients.

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Section: Discussionmentioning

confidence: 99%

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

et al. 2020

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“…In keeping with these findings, defective autophagy pathways in LSEC have been shown to occur in NASH patients compared with controls and steatotic patients. Autophagy deficiency was linked to liver inflammation, EndMT, apoptosis and perisinusoidal fibrosis in a mouse model of NAFLD, outcomes that were independent of metabolic risk factors such as body weight and plasma cholesterol ( Hammoutene et al, 2020 ). Furthermore, activation of autophagy with hypercholesterolaemia drug ezetimibe, via AMPK activation and nuclear translocation of transcription factor TFEB, ameliorated steatohepatitis by dampening inflammasome signalling in macrophages ( Kim et al, 2017 ).…”

Section: Lsec Pathophysiologymentioning

confidence: 99%

“…Aforementioned approaches which could maintain LSEC differentiation and function include restoration of their fenestrated phenotype, via BMP9 and GATA4 ( Geraud et al, 2017 ; Desroches-Castan et al, 2019 ), re-constitution of the VEGF/NO/sGC signalling pathway ( Tateya et al, 2011 ; Xie et al, 2012 ; Marrone et al, 2013 , 2015 ; Wang et al, 2013 ), and re-establishment of normal hedgehog signalling with hedgehog inhibitors such as tetramethylpyrazine ( Zhao et al, 2017 ). Furthermore, maintenance of autophagy pathways, which are known to be important for endothelial homeostasis and are defective in CLD patients ( Hammoutene et al, 2020 ), may offer an additional treatment strategy. Conservation of the LSEC phenotype and prevention of capillarisation may reduce the risk of progression from inflammation and fibrosis to irreversible cirrhosis and HCC.…”

Section: Targeting Lsec In Inflammation and Cancer Therapymentioning

confidence: 99%

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

2020

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Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

“…Autophagy is a highly conserved physiological process controlling endothelial homeostasis in vascular beds [ 26 ]. Studies showed that autophagy defect results in endothelial dysfunction of patients with obesity and metabolic disorders, promoting the progression of ASCVD [ 26 – 28 ]. Fasting is a classical and acknowledged method to regulate autophagy [ 29 – 31 ], which may probably make contributions to EPCs function.…”

Section: Introductionmentioning

confidence: 99%

Fasting Therapy Contributes to the Improvement of Endothelial Function and Decline in Vascular Injury‐Related Markers in Overweight and Obese Individuals via Activating Autophagy of Endothelial Progenitor Cells

Sun

Zhang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Background. High body mass index- (BMI-) related vascular injury contributes to the pathogenesis of the atherosclerotic cardiovascular disease (ASCVD). Rigorous calorie restriction is one of the major lifestyle interventions to reduce vascular risk in overweight or obese individuals. However, the effects of fasting therapy (FT) on vascular function and the mechanism are still unclear. This study was aimed to investigate the impacts of FT on endothelial function, arterial stiffness, and circulating arterial damage parameters in overweight and obese individuals and possible mechanism. Methods. Overweight and obese individuals participated in FT intervention (7-day very low calorie diet). Arterial function including brachial arterial flow-mediated dilation (FMD), brachial-ankle pulse wave velocity (baPWV), vascular injury-related markers including trimethylamine N-oxide (TMAO), and leptin and endothelial microparticles (EMPs) were assessed. Endothelial progenitor cells (EPCs) of these participants were isolated and cultured to investigate EPCs function. mRFP-GFP-LC3 confocal microscopy scanning and western blot were carried out to determine autophagy. Results. After FT, body weight and BMI significantly decreased (81.76 ± 12.04 vs. 77.51 ± 12.06 kg, P<0.01; 29.93 ± 2.82 vs. 28.47 ± 2.83 kg/m2, P<0.01). FT remarkably improved FMD (5.26 ± 1.34 vs. 6.25 ± 1.60%, P=0.01) while baPWV kept unchanged. TMAO and leptin levels decreased (3.96 ± 1.85 vs. 2.73 ± 1.33 μmol/L, P=0.044; 6814 ± 2639 vs. 3563 ± 2668 μmol/L, P<0.01). EMPs showed a decreased tendency. EPCs function was significantly improved, autophagy fluorescence intensity was enhanced, and the level of Beclin1, Atg5, LC3 II/I also increased after starvation in vitro, and the effects were blocked by autophagy inhibitor. Conclusions. Our present study demonstrated for the first time that FT markedly improves endothelial function and reduces the levels of arterial injury markers through improving EPCs function via activating autophagy. These findings provide a novel insight into FT as a lifestyle intervention strategy to promote the maintenance of vascular homeostasis in overweight or obese individuals. The trial was registered with ChiCTR1900024290.

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A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis

Abstract: Deficient autophagy induces inflammation, features of endothelial-to-mesenchymal transition and apoptosis.Deficiency in endothelial autophagy promotes liver inflammation, liver cell apoptosis and liver perisinusoidal fibrosis.

Cited by 129 publications

References 58 publications

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

Fasting Therapy Contributes to the Improvement of Endothelial Function and Decline in Vascular Injury‐Related Markers in Overweight and Obese Individuals via Activating Autophagy of Endothelial Progenitor Cells

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