Abstract:
BACKGROUND & AIMS:Clinical evidence has indicated a close link between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). However, the underlying mechanism remains to be elucidated. This study aimed to explore a potential role of hepatocyte-derived extracellular vesicles (EVs) in endothelial inflammation and atherogenesis in the context of NAFLD. METHODS:EVs were isolated, quantified and characterized from steatotic hepatocytes. An endothelial cell-specific PCR array was used to screen the functional properties of EVs. Profiling of global microRNA expression was conducted in EVs. The expression level and biological function of microRNA-1 (miR-1) was determined by quantitative PCR, immunoblot and reporter gene assays, respectively. The in vivo effect of miR-1 on atherogenesis was investigated in apolipoprotein E (ApoE)-deficient mice administered with a miR-1-specific inhibitor, antagomiR-1. RESULTS:Steatotic hepatocytes released more EVs, which had significantly altered miRNA expression profiles compared to the EVs released by control hepatocytes. Endothelial cells co-cultured with steatotic hepatocytes, or treated with their EVs or miR-1, expressed significantly more proinflammatory molecules, as well as exhibiting increased NF-κB activity and reduced Kruppel-like factor 4 (KLF4) expression. EV-induced endothelial inflammation was prevented by either downregulation or inhibition of miR-1. While miR-1 treatment suppressed KLF4 expression and reporter gene activity, overexpression of KLF4 dramatically abolished the miR-1-induced endothelial inflammation. Moreover, not only did the miR-1 inhibitor reduce endothelial inflammation in vitro, but it also attenuated atherogenesis in ApoE-deficient mice. CONCLUSION:Steatotic hepatocyte-derived EVs promote endothelial inflammation and facilitate atherogenesis by miR-1 delivery, KLF4 suppression and NF-κB activation. The findings illustrate an important role of hepatocyte-derived EVs in distant communications between the liver and vasculature, suggesting a new mechanism underlying the link between NAFLD and CVD. LAY SUMMARY:Non-alcoholic fatty liver disease (NAFLD), a condition highly prevalent in obese and/or diabetic patients, is emerging as an independent risk factor of cardiovascular disease. Herein, we demonstrated that extracellular vesicles, released by hepatocytes under NAFLD conditions, cause vascular endothelial inflammation and promote atherosclerosis. Within these toxic vesicles, we identified a small molecular cargo that acted as a potent inducer of endothelial inflammation. By inhibiting this cargo's function, a specific gene-based inhibitor profoundly attenuated atherogenesis in mice, uncovering a novel mechanism which may be used to prevent or treat cardiovascular disease in patients with NAFLD.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Jiang F,Chen Q,Wang W,Ling Y,Yan Y,Xia Pdoi
10.1016/j.jhep.2019.09.014subject
Has Abstractpub_date
2020-01-01 00:00:00pages
156-166issue
1eissn
0168-8278issn
1600-0641pii
S0168-8278(19)30552-5journal_volume
72pub_type
杂志文章abstract:BACKGROUND/AIMS:Cholangiocarcinoma comprises 5-20% of all primary malignant tumors of the liver. However, the lack of information about the genetic basis of cholangiocarcinoma has impeded characterization and understanding of its biological behavior. METHODS:In this study, genome-wide aberrations in 13 cases of cholan...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(02)00269-6
更新日期:2002-11-01 00:00:00
abstract:BACKGROUND/AIMS:Hepatitis C virus (HCV) is a major etiologic agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The aim of this study was to elucidate pathological effects of HCV-core protein on liver cells. METHODS:We have generated transgenic mice carrying HCV-core cDNA (Px-core) and pathologically...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(00)80280-9
更新日期:2000-09-01 00:00:00
abstract::In recent years a new concept of the mechanism of hepatic fatty acid uptake has been described. It was shown that this major class of energy yielding substrates enters hepatocytes by a carrier-mediated uptake system. After the dissociation of the fatty acid-albumin complex at the sinusoidal liver cell plasma membrane,...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/0168-8278(89)90148-7
更新日期:1989-11-01 00:00:00
abstract:BACKGROUND:Eastern American woodchuck (Marmota monax), naturally infected with woodchuck hepatitis virus, a virus similar to human hepatitis B virus, develops liver cancer with a high prevalence. AIMS:The aim of this work was to assess Marmota monax as a model of human hepatocellular carcinoma, especially to assess ne...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(97)80468-0
更新日期:1997-06-01 00:00:00
abstract::The relationship of the endoscopic aspect of esophageal varices, portal quantitative Doppler ultrasound parameters and clinical and biochemical findings was assessed in 149 patients with cirrhosis stratified according to the presence of esophageal varices (n = 115) and the absence of previous bleeding (n = 96). In thi...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(05)80461-1
更新日期:1994-01-01 00:00:00
abstract::Drug induced hepatotoxicity has been reported infrequently with sulfonylureas. For glimepiride, a second-generation sulfonylurea there is no report of hepatotoxicity in English literature. A patient with non-insulin-dependent diabetes mellitus who developed cholestatic liver injury soon after initiation of glimepiride...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2005.02.011
更新日期:2005-06-01 00:00:00
abstract:BACKGROUND/AIMS:Acyclic retinoid (AR; all trans-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid) prevented hepatocarcinogenesis in animal models and in a randomized clinical trial by eradicating premalignant and latent malignant clones of transformed cells from the liver. We investigated the possible mechanis...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(02)00044-2
更新日期:2002-05-01 00:00:00
abstract::This study evaluates systemic and splanchnic haemodynamics and the effect of propranolol in 15 patients with presinusoidal portal hypertension (portal vein obstruction, n = 11; schistosomiasis, n = 4). These patients exhibited a hyperkinetic circulatory syndrome characterized by high cardiac index (4.4 +/- 1.61.min-1....
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(89)90139-6
更新日期:1989-11-01 00:00:00
abstract:BACKGROUND & AIMS:The primary aim of this study was to compare the rate of global radiofrequency ablation (RFA) failure between monopolar RFA (MonoRFA) vs. no-touch multi-bipolar RFA (NTmbpRFA) for small hepatocellular carcinoma (HCC) ⩽5cm in cirrhotic patients. METHODS:A total of 362 cirrhotic patients were included ...
journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究
doi:10.1016/j.jhep.2016.07.010
更新日期:2017-01-01 00:00:00
abstract:BACKGROUND/AIM:Since patients with high viral load and HCV subtype 1b are known to respond poorly to interferon (IFN) therapy, the viral dynamics of HCV RNA after initiation of interferon therapy were examined in the present study with respect to two different administration regimens, once vs. twice a day. METHODS:Twe...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0168-8278(00)80373-6
更新日期:2000-08-01 00:00:00
abstract:BACKGROUND & AIMS:Most cholesterol gallstones have a core consisting of inorganic and/or organic calcium salts, although the mechanisms of core formation are poorly understood. We examined whether the paracellular permeability of ions at hepatic tight junctions is involved in the core formation of cholesterol gallstone...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.08.025
更新日期:2018-12-01 00:00:00
abstract:BACKGROUND/AIMS:Hepatitis B virus can cause serious problems in individuals undergoing organ transplantation. The aim of this study was to evaluate the hepatic events among HBs-Ag positive recipients and HBs-Ag negative recipients who received products from hepatitis B virus carriers. METHODS:A total of 151 patients r...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80214-1
更新日期:1999-08-01 00:00:00
abstract:BACKGROUND/AIMS:Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published. METHODS:A retrospective analysis was performed of...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.03.010
更新日期:2004-07-01 00:00:00
abstract::The circuitous cell signalling pathways of hepatocytes comprise several factors that operate to downgrade or even interrupt the transmission of a given signal. These down-regulating influences are essential to keep cell proliferation and cell survival in check and if impaired, can alter a delicate balance in favour of...
journal_title:Journal of hepatology
pub_type:
doi:10.1016/j.jhep.2007.09.003
更新日期:2007-12-01 00:00:00
abstract:AIMS/METHODS:During cholestasis, components normally excreted into bile, e.g. bilirubin, accumulate in liver cells and biliary passages. In order to assess the conjugation of bilirubin retained in the hepatocyte during cholestasis, we analyzed the pattern of bilirubin pigments in rat serum and bile, using reversed phas...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(97)80330-3
更新日期:1997-11-01 00:00:00
abstract:BACKGROUND/AIMS:The major regulatory events leading to cell proliferation occur in the G1 phase of cell cycle, and the deranged expression of G1 cyclins is related to oncogenesis. In this study, we analyzed the aberrant expressions of cyclins D1 and E, and their role in hepatocellular carcinoma. METHODS:We examined pa...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(98)80014-7
更新日期:1998-08-01 00:00:00
abstract:BACKGROUND/AIMS:Lamivudine is an antiviral drug that is used to treat hepatitis B virus (HBV) infection. Long-term therapy does not completely suppress viral replication, and resistant mutants emerge. Resistance is mediated by changes in the tyrosine-methionine-apartate-aspartate (YMDD) motif in the catalytic site of t...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.02.009
更新日期:2004-06-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown. METHODS:Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metaboli...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2020.01.023
更新日期:2020-06-01 00:00:00
abstract:BACKGROUND/AIMS:The applicability of adult-to-adult living donor liver transplantation has not been established yet. We report the first data in a European center of the process leading to this procedure from the first moment the patients were informed about it. METHODS:In phase 1 of the process, 121 adult patients en...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2005.02.016
更新日期:2005-07-01 00:00:00
abstract:BACKGROUND & AIMS:Therapeutic options for patients failing hepatitis C retreatment are limited. EPIC(3) included a prospective trial assessing long-term peginterferon alfa-2b (PegIFNα-2b) maintenance therapy in patients with METAVIR fibrosis scores (MFS) of F2 or F3 who previously failed hepatitis C retreatment. METHO...
journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/j.jhep.2012.11.001
更新日期:2013-03-01 00:00:00
abstract::A portal hemodynamic study was made in 7 consecutive patients with chronic portal-systemic encephalopathy by percutaneous transhepatic catheterization of the portal vein and injecting contrast medium into the superior mesenteric vein or by superior mesenteric arterial portography in comparison with patients without en...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(85)80745-5
更新日期:1985-01-01 00:00:00
abstract::Familial hypobetalipoproteinemia (FHBL) is an monogenic co-dominant disorder characterized by reduced plasma levels of cholesterol, low density lipoproteins (LDL) and apolipoprotein B (apoB) often associated with non-alcoholic fatty liver disease (NAFLD). It has been suggested that FHBL might predispose to gallstone d...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2005.03.012
更新日期:2005-07-01 00:00:00
abstract:BACKGROUND/AIMS:The world-wide distribution of hepatitis B virus (HBV) genotypes follows a geographic pattern under the influence of ethnic background. METHODS:Forty eight core genes from four pacific islands were compared with the following findings. RESULTS:First, island-specific variant substitutions were found fo...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.03.025
更新日期:2004-07-01 00:00:00
abstract::Hepatitis A virus (HAV) infection in adults is often symptomatic and disabling. The present article summarizes our experience with phase 2 studies of an inactivated hepatitis A virus vaccine. Pre- and post-exposure prophylaxis with immune globulin (IG) is only effective for 4-6 months. We compared the safety, tolerabi...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0168-8278(05)80375-7
更新日期:1993-01-01 00:00:00
abstract:BACKGROUND & AIMS:Data from clinical trials suggest a potential role for on-treatment monitoring of serum HBsAg titres during interferon-alpha (pegIFN) therapy in predicting virological responses. However, baseline HBsAg titres during the natural history of chronic hepatitis B (CHB) have not been well-characterized. We...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1016/j.jhep.2010.01.007
更新日期:2010-04-01 00:00:00
abstract:BACKGROUND/AIMS:The development of cholesterol gallstones, in some patients, has been associated with increased proportions of deoxycholic acid in the bile acid pool. Deoxycholic acid is a microbial product of cholic acid 7alpha-dehydroxylation in the intestines. The levels and activities of bile acid 7alpha-dehydroxyl...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(00)80183-x
更新日期:2000-01-01 00:00:00
abstract:BACKGROUND/AIMS:In order to prevent the occurrence of drug-resistant mutants associated with treatment for chronic hepatitis B virus (HBV) infection, combination therapy is being developed. To determine the efficacy of adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy in chronic HBV infection. METH...
journal_title:Journal of hepatology
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.jhep.2007.10.013
更新日期:2008-05-01 00:00:00
abstract::Intravascular coagulation is involved in the development of certain types of liver injury, including that induced by dimethylnitrosamine. Nitric oxide inhibits platelet aggregation and adhesion; however, its role in protecting against intravascular coagulation has not been clarified. We therefore investigated the effe...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(95)80068-9
更新日期:1995-11-01 00:00:00
abstract::Secondary biliary cirrhosis in the rat is an attractive model since unlike other models it does not rely on exogenous toxic compounds to induce cirrhosis. However, because little is known about the microcirculatory abnormalities of this model, this study investigated hemodynamics in rats with predefined functional imp...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(05)80031-5
更新日期:1993-02-01 00:00:00
abstract:BACKGROUND/AIMS:The aim of this study is to verify the efficacy and safety of peg-interferon alfa-2b in combination with ribavirin for initial treatment of HCV-associated mixed cryoglobulinemia. METHODS:Eighteen patients (7 women and 11 men) affected by mixed cryoglobulinemia were included in the study and treated wit...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/j.jhep.2004.10.031
更新日期:2005-05-01 00:00:00