Abstract:
BACKGROUND & AIMS:Autophagy plays a crucial role in hepatic homeostasis and its deregulation has been associated with chronic liver disease. However, the effect of autophagy on the release of fibrogenic extracellular vesicles (EVs) by platelet-derived growth factor (PDGF)-stimulated hepatic stellate cells (HSCs) remains unknown. Herein, we aimed to elucidate the role of autophagy, specifically relating to fibrogenic EV release, in fibrosis. METHODS:In vitro experiments were conducted in primary human and murine HSCs as well as LX2 cells. Small EVs were purified by differential ultracentrifugation. Carbon tetrachloride (CCl4) or bile duct ligation (BDL) were used to induce fibrosis in our mouse model. Liver lysates from patients with cirrhosis or healthy controls were compared by RNA sequencing. RESULTS:In vitro, PDGF and its downstream molecule SHP2 (Src homology 2-containing protein tyrosine phosphatase 2) inhibited autophagy and increased HSC-derived EV release. We used this PDGF/SHP2 model to further investigate how autophagy affects fibrogenic EV release. RNA sequencing identified an mTOR (mammalian target of rapamycin) signaling molecule that was regulated by SHP2 and PDGF. Disruption of mTOR signaling abolished PDGF-dependent EV release. Activation of mTOR signaling induced the release of multivesicular body-derived exosomes (by inhibiting autophagy) and microvesicles (by activating ROCK1 signaling). These mTOR-dependent EVs promoted in vitro HSC migration. To assess the importance of this mechanism in vivo, SHP2 was selectively deleted in HSCs, which attenuated CCl4- or BDL-induced liver fibrosis. Furthermore, in the CCl4 model, mice receiving circulating EVs derived from mice with HSC-specific Shp2 deletion had less fibrosis than mice receiving EVs from control mice. Correspondingly, SHP2 was upregulated in patients with liver cirrhosis. CONCLUSION:These results demonstrate that autophagy in HSCs attenuates liver fibrosis by inhibiting the release of fibrogenic EVs. LAY SUMMARY:During liver fibrosis and cirrhosis, activated hepatic stellate cells (HSCs) are the key cell type responsible for fibrotic tissue deposition. Recently, we demonstrated that activated HSCs release nano-sized vesicles enriched with fibrogenic proteins. In the current study, we unveil the mechanism by which these fibrogenic vesicles are released, moving a step closer to the long-term goal of therapeutically targeting this process.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Gao J,Wei B,de Assuncao TM,Liu Z,Hu X,Ibrahim S,Cooper SA,Cao S,Shah VH,Kostallari Edoi
10.1016/j.jhep.2020.04.044subject
Has Abstractpub_date
2020-11-01 00:00:00pages
1144-1154issue
5eissn
0168-8278issn
1600-0641pii
S0168-8278(20)30290-7journal_volume
73pub_type
杂志文章abstract::Surveillance of patients at risk of developing hepatocellular carcinoma (HCC) is based on ultrasound (US) examinations performed at either 6 or 12 month intervals. Early detection of HCC in patients with cirrhosis is a challenging issue, since the different entities that are involved in the multi-step process of hepat...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2008.02.005
更新日期:2008-05-01 00:00:00
abstract:BACKGROUND AND AIMS:Fatty acid translocase CD36 (CD36) is a membrane protein with multiple immuno-metabolic functions. Palmitoylation has been suggested to regulate the distribution and functions of CD36, but little is known about its significance in non-alcoholic steatohepatitis (NASH). METHODS:Human liver tissue sam...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.04.006
更新日期:2018-09-01 00:00:00
abstract::To establish the effects of a meal on portal venous flow and the prognostic value of this parameter, 46 patients with chronic liver disease and 28 healthy subjects were examined with duplex Doppler before and after a meal. The measurements were completed in 40 patients and 21 healthy subjects. Postprandial portal veno...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(05)80603-8
更新日期:1994-12-01 00:00:00
abstract:BACKGROUND/AIMS:The efficacy of anti-viral therapy for chronic hepatitis B virus (HBV) is lost upon the emergence of resistant virus. Using >500 patient HBV isolates from several entecavir clinical trials, we show that phenotypic susceptibility correlates with genotypic resistance and patient virologic responses. METH...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2007.12.024
更新日期:2008-06-01 00:00:00
abstract:BACKGROUND/AIMS:Primary sclerosing cholangitis (PSC) is associated with a high risk of cholangiocarcinoma development. Efforts should be made to detect early neoplastic changes that can be radically treated by liver transplantation. METHODS:In this prospective case series we obtained brush cytology specimens from bile...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/j.jhep.2006.05.010
更新日期:2006-10-01 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:Hallmarks of non-alcoholic fatty liver disease (NAFLD) are increased triglyceride accumulation within hepatocytes. The prevalence of NAFLD increases steadily with increasing thyrotropin (TSH) levels. However, the underlying mechanisms are largely unknown. Here, we focused on exploring the effect and m...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2014.06.037
更新日期:2014-12-01 00:00:00
abstract:BACKGROUND/AIMS:HCV infection recurs almost in all HCV-positive patients receiving liver transplantation and carries a poor prognosis. Aim of this study was to analyze efficacy and effect on survival of antiviral therapy in this clinical setting. METHODS:Pegylated-interferon alpha-2b and ribavirin were administered at...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/j.jhep.2006.10.017
更新日期:2007-03-01 00:00:00
abstract:BACKGROUND/AIMS:Not all alcoholic patients develop severe liver disease with fibrosis progressing to cirrhosis. It is of practical importance to determine whether some markers can predict progression of liver fibrosis. METHODS:We used a baboon model that mimics human alcoholic liver disease. Cytokeratin 7 and 19 expre...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(03)00144-2
更新日期:2003-06-01 00:00:00
abstract:BACKGROUND & AIMS:Alcoholic hepatitis is an acute life- and health-threatening disease that may be increasingly frequent. However, accurate and representative data on time trends in its incidence and prognosis are not available. This study aims to provide nationwide population-based estimates of alcoholic hepatitis inc...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2010.07.016
更新日期:2011-04-01 00:00:00
abstract:BACKGROUND/AIMS:In this study, a detailed morphometrical analysis of the hepatic microvasculature in the different zones of hepatic parenchyma was performed in normal and cirrhotic rat liver (CCl4-induced). The aims were to detect, in CCl4-induced cirrhosis, the real presence of the "capillarization" of hepatic sinusoi...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1034/j.1600-0641.2000.033004555.x
更新日期:2000-10-01 00:00:00
abstract:BACKGROUND/AIMS:Liver fibrosis is a dynamic state between matrix production and degradation. Since our report in 1974, many studies have examined collagenase and liver fibrosis, but not the identification of cells responsible for collagenase production in vivo. The aim of this study was to investigate the gene expressi...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(00)80363-3
更新日期:2000-08-01 00:00:00
abstract:BACKGROUND & AIMS:The liver is the main hematopoietic site in embryos, becoming a crucial organ in both immunity and metabolism in adults. However, how the liver adapts both the immune system and enzymatic profile to challenges in the postnatal period remains elusive. We aimed to identify the mechanisms underlying this...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.08.018
更新日期:2018-12-01 00:00:00
abstract:BACKGROUND/AIMS:In primary biliary cirrhosis (PBC), pathogenesis is influenced by genetic factors that remain poorly elucidated up to now. We investigated the impact of sequence diversity in candidate genes involved in immunity (CTLA-4 and TNFalpha), in bile formation (10 hepatobiliary transporter genes) and in the ada...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2008.07.027
更新日期:2008-12-01 00:00:00
abstract::TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies invivo, we show here that TGR5 sign...
journal_title:Journal of hepatology
pub_type: 评论,杂志文章
doi:10.1016/j.jhep.2010.02.003
更新日期:2010-06-01 00:00:00
abstract::The burden of hepatocellular carcinoma (HCC) is highest in East Asia and Africa, although its incidence and mortality are rapidly rising in the United States and Europe. With the implementation of hepatitis B vaccination and hepatitis C treatment programmes worldwide, the epidemiology of HCC is shifting away from a di...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2019.08.025
更新日期:2020-02-01 00:00:00
abstract:BACKGROUND & AIMS:Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhos...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.10.027
更新日期:2019-03-01 00:00:00
abstract:BACKGROUND/AIMS:Hepatobiliary malignancies are frequently seen in primary sclerosing cholangitis (PSC) and they complicate the evaluation of patients and timing of liver transplantation. METHODS:Data from all Nordic PSC patients listed for liver transplantation during 1990-2001 were recorded prospectively. Predictors ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.01.002
更新日期:2004-05-01 00:00:00
abstract:BACKGROUND & AIMS:Large extracellular vesicles, specifically AnnexinV+ EpCAM+ CD147+ tumour-associated microparticles (taMPs), facilitate the detection of colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) as well as pancreas carcinoma (PaCa). Here we assess the diagnostic value of taMPs for detection an...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2017.02.024
更新日期:2017-08-01 00:00:00
abstract::We describe a new model of submaximal stimulation of liver regeneration in the rat. Removal of the right lateral lobes in the rat produced a 21% hepatectomy. The measurement accuracy of the incorporation rate of [14C]thymidine into DNA 24 h after 21% hepatectomy (n = 32) was less than that after the standard 34% hepat...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(91)90833-w
更新日期:1991-05-01 00:00:00
abstract::The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with a...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2013.07.014
更新日期:2013-12-01 00:00:00
abstract:BACKGROUND & AIMS:Ventriculo-arterial coupling (VAC) reflects the interaction between ventricular performance and effective arterial load. Current criteria for cirrhotic cardiomyopathy focus only on cardiac function without addressing the effect of hyperdynamic, low-resistance circulation. We investigated alterations i...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2016.09.009
更新日期:2017-02-01 00:00:00
abstract::The integrated results of a worldwide clinical research program studying interferon-alpha 2a (IFN-alpha 2a) (Roferon-A, F. Hoffmann-La Roche Ltd, Basel, Switzerland) for the treatment of chronic hepatitis C in 1831 patients are reviewed in this paper. According to a multivariate analysis of the data available from thi...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1995-01-01 00:00:00
abstract:BACKGROUND/AIMS:Partial hepatectomy results in activation of genes in the residual liver tissue which serve to restore glucose homeostasis and regenerate liver mass. Expression of insulin-like growth factor binding protein-1 (IGFBP-1) is up-regulated following partial hepatectomy and IGFBP-1 can modulate both the metab...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80199-8
更新日期:1999-04-01 00:00:00
abstract:BACKGROUND/AIMS:We reported that reduced dietary intake of polyunsaturated fatty acids (PUFA) such as arachidonic (AA,20:4n6,omega-6) and docosahexaenoic (DHA,22:6n3,omega-3) acids led to alcohol-induced fatty liver and fibrosis. This study was aimed at studying the mechanisms by which a DHA/AA-supplemented diet preven...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2008.04.023
更新日期:2008-08-01 00:00:00
abstract::The First European Consensus Conference on the Treatment of Chronic Hepatitis B and C in HIV Co-infected Patients aimed to produce recommendations that could be applied across Europe. However, some important differences exist around Europe, in terms of access to treatment and tests for monitoring. This short survey of...
journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究
doi:10.1016/j.jhep.2005.11.034
更新日期:2006-01-01 00:00:00
abstract:BACKGROUND & AIMS:Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a prospective randomized co...
journal_title:Journal of hepatology
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.jhep.2016.03.003
更新日期:2016-08-01 00:00:00
abstract:BACKGROUND & AIMS:Primary non-function and ischaemic cholangiopathy are the most feared complications following donation-after-circulatory-death (DCD) liver transplantation. The aim of this study was to design a new score on risk assessment in liver-transplantation DCD based on donor-and-recipient parameters. METHODS:...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2017.10.034
更新日期:2018-03-01 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::Interferon-alpha therapy has a beneficial effect in 30-40% of selected patients with chronic hepatitis B who respond by clearing hepatitis B e antigen (HBeAg) and hepatitis B viral (HBV) DNA from serum. This is usually associated with normalization of serum aminotransferase activities. On long-term follow-up of treate...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:
更新日期:1995-01-01 00:00:00