Abstract:
BACKGROUND & AIMS:The pathomechanisms underlying non-alcoholic fatty liver disease (NAFLD) and the involved molecular regulators are incompletely explored. The nuclear factor-kappa B (NF-κB)-cofactor gene B cell leukemia-3 (Bcl-3) plays a critical role in altering the transcriptional capacity of NF-κB - a key inducer of inflammation - but also of genes involved in cellular energy metabolism. METHODS:To define the role of Bcl-3 in non-alcoholic steatohepatitis (NASH), we developed a novel transgenic mouse model with hepatocyte-specific overexpression of Bcl-3 (Bcl-3Hep) and employed a high-fat, high-carbohydrate dietary feeding model. To characterize the transgenic model, deep RNA sequencing was performed. The relevance of the findings was confirmed in human liver samples. RESULTS:Hepatocyte-specific overexpression of Bcl-3 led to pronounced metabolic derangement, characterized by enhanced hepatic steatosis from increased de novo lipogenesis and uptake, as well as decreased hydrolysis and export of fatty acids. Steatosis in Bcl-3Hep mice was accompanied by an augmented inflammatory milieu and liver cell injury. Moreover, Bcl-3 expression decreased insulin sensitivity and resulted in compensatory regulation of insulin-signaling pathways. Based on in vivo and in vitro studies we identified the transcription factors PPARα, PPARγ and PGC-1α as critical regulators of hepatic metabolism and inflammation downstream of Bcl-3. Metformin treatment improved the metabolic and inflammatory phenotype in Bcl-3Hep mice through modulation of PPARα and PGC-1α. Remarkably, these findings were recapitulated in human NASH, which exhibited increased expression and nuclear localization of Bcl-3. CONCLUSIONS:In summary, Bcl-3 emerges as a novel regulator of hepatic steatosis, insulin sensitivity and inflammation in NASH. LAY SUMMARY:Non-alcoholic fatty liver disease (NAFLD) is considered the most prevalent liver disease worldwide. Patients can develop end-stage liver disease resulting in liver cirrhosis or hepatocellular carcinoma, but also develop complications unrelated to liver disease, e.g., cardiovascular disease. Still there is no full understanding of the mechanisms that cause NAFLD. In this study, genetically engineered mice were employed to examine the role of a specific protein in the liver that is involved in inflammation and the metabolism, namely Bcl-3. By this approach, a better understanding of the mechanisms contributing to disease progression was established. This can help to develop novel therapeutic and diagnostic options for patients with NAFLD.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Gehrke N,Wörns MA,Huber Y,Hess M,Straub BK,Hövelmeyer N,Waisman A,Kim YO,Schuppan D,Galle PR,Schattenberg JMdoi
10.1016/j.jhep.2016.06.026subject
Has Abstractpub_date
2016-12-01 00:00:00pages
1188-1197issue
6eissn
0168-8278issn
1600-0641pii
S0168-8278(16)30322-1journal_volume
65pub_type
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abstract::In order to evaluate age at menopause and serum sex hormone profiles in postmenopausal women with stable chronic liver disease, six non-cirrhotic alcoholics, 13 with alcoholic cirrhosis, eight with non-alcoholic cirrhosis, and 46 healthy controls were studied. In all three groups, patients were significantly (p less t...
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doi:10.1016/0168-8278(91)90859-a
更新日期:1991-07-01 00:00:00
abstract:BACKGROUND/AIMS:Norfloxacin is useful to prevent infections in hospitalized cirrhotic patients with low ascitic fluid protein concentrations. It is also effective in preventing the recurrence of spontaneous bacterial peritonitis. The aim of our study was to determine the efficacy of norfloxacin in the primary prophylax...
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pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1016/s0168-8278(98)80061-5
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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 ...
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doi:10.1016/j.jhep.2011.03.030
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abstract:BACKGROUND:NGM282, an engineered analogue of the gut hormone FGF19, improves hepatic steatosis and fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH). However, NGM282 increases serum cholesterol levels by inhibiting CYP7A1, which encodes the rate-limiting enzyme in the conversion of cholesterol t...
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更新日期:2019-04-01 00:00:00
abstract::Recently, we have shown that taurocholate transport is impaired in hepatocytes isolated from CCl4 cirrhotic rats. Na+,K+-ATPase activity depends on the lipid composition of the surrounding membrane. Therefore, we performed this study in order to detect differences in plasma membrane composition and membrane functions ...
journal_title:Journal of hepatology
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journal_title:Journal of hepatology
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更新日期:1994-03-01 00:00:00
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journal_title:Journal of hepatology
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doi:10.1016/j.jhep.2006.10.010
更新日期:2007-04-01 00:00:00
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更新日期:1999-11-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.jhep.2012.05.021
更新日期:2012-10-01 00:00:00
abstract:BACKGROUND & AIMS:Inflammatory gene expression plays a pathological role in acute and chronic hepatic inflammation, yet, inflammation also promotes liver repair by inducing protective mechanisms to limit collateral tissue damage by priming hepatocytes for proliferation. Early growth response (Egr)-1, a transcription fa...
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pub_type: 杂志文章
doi:10.1016/j.jhep.2010.04.017
更新日期:2010-10-01 00:00:00
abstract:BACKGROUND & AIMS:Direct-acting antiviral (DAA) therapy is used in patients with HCV-related decompensated cirrhosis with the expectation of improving hepatic function. However, little is known about the long-term hepatic benefit of successful antiviral treatment. METHODS:Patients with advanced/decompensated cirrhosis...
journal_title:Journal of hepatology
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doi:10.1016/j.jhep.2020.03.031
更新日期:2020-09-01 00:00:00
abstract::In situ hybridization with oligonucleotide probes has been used to localise hepatitis A virus RNA genomic sequences in formalin-fixed and routinely processed human liver biopsies from three patients. Using radiolabelled Sulphur-35 antisense probes, viral genomic sequences were found in all three cases, but signal inte...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(94)80012-x
更新日期:1994-03-01 00:00:00
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更新日期:2018-11-01 00:00:00
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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::This article has been withdrawn at the request of the authors and with approval of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. ...
journal_title:Journal of hepatology
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doi:10.1016/j.jhep.2010.12.044
更新日期:2011-02-22 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2005-02-01 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,多中心研究
doi:10.1016/j.jhep.2016.07.010
更新日期:2017-01-01 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.2013.09.009
更新日期:2014-02-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into t...
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pub_type: 杂志文章
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更新日期:2020-11-25 00:00:00
abstract::alpha-Interferon therapy normalizes aminotransferase levels in approximately 50% of the patients with chronic hepatitis C, but post-therapy relapses are common and predictive factors of sustained response remain largely unknown. We retrospectively assessed several parameters as predictors of sustained remission after ...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/s0168-8278(94)80129-0
更新日期:1994-07-01 00:00:00