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 samples were obtained from patients undergoing liver biopsy for diagnostic purposes. CD36 knockout mice were injected with lentiviral vectors expressing wild-type CD36 or CD36 with mutated palmitoylation sites. Liver histology, immunofluorescence, mRNA expression profile, subcellular distributions and functions of CD36 protein were assessed. RESULTS:The localization of CD36 on the plasma membrane of hepatocytes was markedly increased in patients with NASH compared to patients with normal liver and those with simple steatosis. Increased CD36 palmitoylation and increased localization of CD36 on the plasma membrane of hepatocytes were also observed in livers of mice with NASH. Furthermore, inhibition of CD36 palmitoylation protected mice from developing NASH. The absence of palmitoylation decreased CD36 protein hydrophobicity reducing its localization on the plasma membrane as well as in lipid raft of hepatocytes. Consequently, a lack of palmitoylation decreased fatty acid uptake and CD36/Fyn/Lyn complex in HepG2 cells. Inhibition of CD36 palmitoylation not only ameliorated intracellular lipid accumulation via activation of the AMPK pathway, but also inhibited the inflammatory response through the inhibition of the JNK signaling pathway. CONCLUSIONS:Our findings demonstrate the key role of palmitoylation in regulating CD36 distributions and its functions in NASH. Inhibition of CD36 palmitoylation may represent an effective therapeutic strategy in patients with NASH. LAY SUMMARY:Fatty acid translocase CD36 (CD36) is a multifunctional membrane protein which contributes to the development of liver steatosis. In the present study, we demonstrated that the localization of CD36 on the plasma membrane of hepatocytes is increased in patients with non-alcoholic steatohepatitis. Blocking the palmitoylation of CD36 reduces CD36 distribution in hepatocyte plasma membranes and protects mice from non-alcoholic steatohepatitis. The inhibition of CD36 palmitoylation not only improved fatty acid metabolic disorders but also reduced the inflammatory response in vitro and in vivo. The present study suggests that CD36 palmitoylation is important for non-alcoholic steatohepatitis development and inhibition of CD36 palmitoylation could be used to cure non-alcoholic steatohepatitis.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Zhao L,Zhang C,Luo X,Wang P,Zhou W,Zhong S,Xie Y,Jiang Y,Yang P,Tang R,Pan Q,Hall AR,Luong TV,Fan J,Varghese Z,Moorhead JF,Pinzani M,Chen Y,Ruan XZdoi
10.1016/j.jhep.2018.04.006subject
Has Abstractpub_date
2018-09-01 00:00:00pages
705-717issue
3eissn
0168-8278issn
1600-0641pii
S0168-8278(18)32014-2journal_volume
69pub_type
杂志文章abstract::The development of portal hypertension is a common consequence of chronic liver diseases leading to the formation of esophageal and gastric varices responsible for variceal bleeding, associated with a high mortality rate, as well as other severe complications such as portosystemic encephalopathy and sepsis. Measuremen...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
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abstract:BACKGROUND/AIMS:To bridge acute liver failure (ALF) patients to orthotopic liver transplantation, several bioartificial liver (BAL) systems have been developed. The bio-component of most BAL systems consists mainly of porcine hepatocytes. Plasma or blood of ALF patients is perfused through the BAL thereby contacting po...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.11.041
更新日期:2005-04-01 00:00:00
abstract::The nucleocapsid antigens (HBc and HBe) are present on the membranes of HBV-infected hepatocytes from HBV carriers. In autologous cytotoxicity experiments we demonstrate that cytotoxic T cells sensitised to the nucleocapsid proteins of hepatitis B are present in HBe antigen-positive HBV carriers with chronic hepatitis...
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doi:10.1016/s0168-8278(87)80004-1
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doi:10.1016/0168-8278(95)80311-4
更新日期:1995-07-01 00:00:00
abstract:BACKGROUND & AIMS:To prospectively assess the diagnostic accuracy of the incorporation of additional magnetic resonance imaging (MRI) parameters in those based on contrast enhancement pattern for the diagnosis of solitary nodules between 5 and 20mm, detected during surveillance in patients with cirrhosis. METHODS:Betw...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2012.01.004
更新日期:2012-06-01 00:00:00
abstract:BACKGROUND/AIMS:Health-related quality of life (HRQoL) is impaired in patients with chronic hepatitis C. We investigated HRQoL and fatigue in patients with chronic hepatitis C virus (HCV) infection in relation to the degree of fibrosis and inflammation, and controlled for the influence of relevant demographic and medic...
journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究
doi:10.1016/j.jhep.2008.07.025
更新日期:2008-12-01 00:00:00
abstract::A joint EASL/AASLD Monothematic Conference on 'Nuclear Receptors and Liver Disease' was held from February 27th to March 1st, 2009, in Vienna, Austria, to discuss the latest advances at the forefront of basic and clinical nuclear receptor research and its potential implications for liver diseases. This article reports...
journal_title:Journal of hepatology
pub_type:
doi:10.1016/j.jhep.2009.12.002
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abstract:BACKGROUND/AIMS:Thrombin and MC tryptase, which are agonists for proteinase-activated receptors-1 and -2, respectively, are both increased in injured liver. We have examined if rat stellate cells express these receptors and if receptor agonists influence stellate cell activation. METHODS:Expression of mRNA for protein...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(01)00285-9
更新日期:2002-03-01 00:00:00
abstract::The Hepatitis Delta Virus (HDV), a defective ribonucleic acid virus dependent on the Hepatitis B Virus (HBV) is a cause of severe liver disease that often leads to cirrhosis and death. Since the HDV finds in the HBV infection a biological niche in which to thrive indefinitely, the major victims of its infection are th...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1986-01-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2005.01.028
更新日期:2005-06-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2011.03.024
更新日期:2011-12-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatitis C virus (HCV) incidence among HIV-positive men who have sex with men (MSM) has increased since 2000, although there are regional differences. We aimed to 1) estimate trends in HCV incidence among HIV-positive MSM, 2) assess the association between incidence and geographical region, age and H...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2017.03.038
更新日期:2017-08-01 00:00:00
abstract:BACKGROUND & AIMS:Therapy of chronic hepatitis B with HBV-polymerase inhibitors, in particular tenofovir or adefovir, may affect renal function. To assess renal function more accurately in the normal range, we used the recently validated, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula to calculate ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2011.03.030
更新日期:2011-12-01 00:00:00
abstract:BACKGROUND/AIMS:Repetitive indomethacin administration induces down-regulation of hepatic cytochrome P450 (CYP) enzymes. We tested the hypothesis that an increase in intestinal permeability by indomethacin-induced intestinal injury leads to entry of bacterial endotoxin and reaching into liver via the portal vein, resul...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(03)00244-7
更新日期:2003-09-01 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:Hepatitis B virus (HBV) has developed strategies to evade immune responses. However, the mechanisms involved remain unclear. The NLRP3 inflammasome plays crucial roles in antiviral host defense and its downstream factor IL-1β has been shown to inhibit HBV infection in vivo. This study aims to assess w...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2016.12.018
更新日期:2017-04-01 00:00:00
abstract:BACKGROUND & AIMS:Non alcoholic steatohepatitis (NASH) has no approved pharmacological therapy. Insulin sensitisers such as thiazolidinediones ameliorate insulin resistance and are a potential therapeutic option. We performed a systematic review and meta-analysis of the effect of thiazolidinediones on histological and ...
journal_title:Journal of hepatology
pub_type: 杂志文章,meta分析,评审
doi:10.1016/j.jhep.2011.03.016
更新日期:2011-12-01 00:00:00
abstract:BACKGROUND & AIMS:Liver stiffness (LS) as measured by transient elastography [Fibroscan] offers a novel non-invasive approach to assess liver cirrhosis. Since Fibroscan seems to be unreliable in patients with congestive heart failure, it remains to be determined whether hemodynamic changes affect LS irrespective of fib...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.11.018
更新日期:2010-02-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究
doi:10.1016/j.jhep.2011.11.022
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2013.04.011
更新日期:2013-08-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0168-8278(05)80215-6
更新日期:1993-03-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2020.08.009
更新日期:2021-01-01 00:00:00
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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
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journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究
doi:10.1016/j.jhep.2010.07.011
更新日期:2011-02-01 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
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2010.12.040
更新日期:2011-10-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2020.07.014
更新日期:2020-12-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2012.01.007
更新日期:2012-06-01 00:00:00
abstract:BACKGROUND/AIMS:Type 2 autoimmune hepatitis (AIH) is characterized by the presence of anti-liver kidney microsome (anti-LKM-1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies. However, the correlation between these autoantibodies and the genetic background has not been studied. METHODS:Frequencies of HLA cl...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2006.07.034
更新日期:2006-12-01 00:00:00
abstract:BACKGROUND & AIMS:Although liver fibrosis is an important predictor of outcomes for biliary atresia (BA), postsurgical native liver histology has not been well reported. Here, we retrospectively evaluated postsurgical native liver histology, and developed and assessed a novel scoring system - the BA liver fibrosis (BAL...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2014.01.028
更新日期:2014-06-01 00:00:00