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 metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2Act-hep mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7Δhep) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology. RESULTS:Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly. CONCLUSIONS:NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors. LAY SUMMARY:Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
He F,Antonucci L,Yamachika S,Zhang Z,Taniguchi K,Umemura A,Hatzivassiliou G,Roose-Girma M,Reina-Campos M,Duran A,Diaz-Meco MT,Moscat J,Sun B,Karin Mdoi
10.1016/j.jhep.2020.01.023subject
Has Abstractpub_date
2020-06-01 00:00:00pages
1182-1195issue
6eissn
0168-8278issn
1600-0641pii
S0168-8278(20)30070-2journal_volume
72pub_type
杂志文章abstract:AIM/METHODS:To elucidate the metabolic effect of interferon alpha, the following tests were performed on 14 patients with chronic active hepatitis C before and after interferon therapy (6 million units/day for 2 weeks): (1) oral glucose tolerance tests to measure insulin secretion; (2) euglycemic hyperinsulinemic clamp...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/0168-8278(88)80004-7
更新日期:1998-02-01 00:00:00
abstract:BACKGROUND & AIMS:Recent studies have suggested that insulin resistance exerts a strong influence on chronic hepatitis C virus (HCV) infection. We analyzed pretreatment factors useful for predicting sustained virological response (SVR), especially interleukin (IL) 28B polymorphism and Homeostasis Model Assessment of In...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2012.04.027
更新日期:2012-09-01 00:00:00
abstract:BACKGROUND & AIMS:The liver is a crucial organ at the crossroads of iron and glucose metabolism. The aim of the study was to assess intra-hepatic iron in young patients with non-alcoholic fatty liver disease (NAFLD) and its association with insulin resistance and severity of liver damage. METHODS:Intrahepatic iron con...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2010.12.007
更新日期:2011-09-01 00:00:00
abstract:BACKGROUND:Platelet cytosolic calcium is necessary for normal platelet function, and may reflect intracellular signalling in vascular smooth muscle cells. METHODS:The cytosolic calcium of platelets from patients with cirrhosis and control subjects was measured in contact with plasma from either source, using FURA 2AM....
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(96)80117-6
更新日期:1996-09-01 00:00:00
abstract:BACKGROUND/AIMS:IgM antibodies to hepatitis C virus have been found in a variable proportion of patients with chronic hepatitis C. We have evaluated whether IgM anti-core antibodies correlate with viraemia or hepatic injury in chronic hepatitis C. METHODS:Serum from 106 patients with chronic hepatitis C with varying s...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(96)80181-4
更新日期:1996-01-01 00:00:00
abstract::Human serum albumin (HSA) is one of the most frequent treatments in patients with decompensated cirrhosis. Prevention of paracentesis-induced circulatory dysfunction, prevention of type-1 HRS associated with bacterial infections, and treatment of type-1 hepatorenal syndrome are the main indications. In these indicatio...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2014.04.012
更新日期:2014-08-01 00:00:00
abstract:BACKGROUND & AIMS:The incidence of cirrhosis and subsequent development of organ dysfunction (OD) requiring intensive care unit (ICU) support is rising. Historically, critically ill cirrhotics are perceived as having poor prognosis and substantial cost of care. METHODS:The aim was to prospectively analyse resource uti...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2011.12.014
更新日期:2012-05-01 00:00:00
abstract::All routinely available assays to detect hepatitis C virus (HCV) infection are based on the specific reaction of serum antibodies to corresponding viral antigens. The only method to detect viral nucleic acids in serum or liver is the enzymatic amplification of reversely transcribed HCV-RNA by polymerase chain reaction...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(92)90074-y
更新日期:1992-07-01 00:00:00
abstract:BACKGROUND/AIMS:Chronic hepatitis C virus infections are often associated with extra-hepatic immunological manifestations, including various autoimmune disorders. The aims of this study were: (i) to determine the prevalence of hepatitis C virus markers in patients with autoimmune thrombocytopenic purpura, and (ii) to d...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(95)80027-1
更新日期:1995-12-01 00:00:00
abstract:BACKGROUND/AIMS:Leptin has a particular profibrogenic role in the liver. We investigated whether IFN-alpha influences leptin production in patients with chronic hepatitis B (CHB) and C (CHC). Leptin was determined in serial samples from 63 CHB and 42 CHC IFN-alpha treated patients. Furthermore, we evaluated whether lep...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2006.01.025
更新日期:2006-05-01 00:00:00
abstract::To evaluate the efficacy of recombinant interferon alpha-2b in the treatment of patients with acute post-transfusion hepatitis C, a randomized controlled trial was conducted in 33 acute post-transfusion hepatitis C patients; 16 patients received 3 million units of subcutaneously injected recombinant interferon alpha-2...
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(94)80246-7
更新日期:1994-11-01 00:00:00
abstract:BACKGROUND & AIMS:It was recently shown that semi-annual surveillance for hepatocellular carcinoma (HCC) in cirrhotic patients provides a prognostic advantage over the annual program; however, its cost-effectiveness (CE) in the general cirrhotic population still needs to be defined. METHODS:A Markov model was built to...
journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究
doi:10.1016/j.jhep.2011.11.022
更新日期:2012-05-01 00:00:00
abstract:BACKGROUND/AIMS:Liver allograft is known to protect simultaneously transplanted organs from acute rejection. We have reported that only 6% of combined liver-kidney recipients, versus 32.5% of kidney recipients, develop kidney graft acute rejection. Release of soluble human leukocyte antigen (HLA) molecules by the liver...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(03)00354-4
更新日期:2003-10-01 00:00:00
abstract:BACKGROUND/AIMS:The pathogenesis of the inflammatory lesion in primary sclerosing cholangitis is unknown. The clinical picture is characterized by i.a. episodes of fever, the cause of which also remains speculative. Previous studies of bacterial isolates in the liver or bile ducts in primary sclerosing cholangitis have...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(98)80316-4
更新日期:1998-03-01 00:00:00
abstract:BACKGROUND/AIMS:Excessive formation of nitric oxide may mediate the generalized vasorelaxation and hyporesponsiveness to vasoconstrictors observed in portal hypertensive states. Endotoxin, released from the bowel and detoxified by the liver, could stimulate inducible nitric oxide synthase directly or indirectly via the...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80266-9
更新日期:1999-06-01 00:00:00
abstract:BACKGROUND/AIMS:Hepcidin is a liver-expressed peptide which plays an important role in the regulation of iron metabolism. It is a negative regulator of iron absorption and release of iron from cells. The aims of this study were to analyse the expression and localisation of prohepcidin in liver and cell lines. METHODS:...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2005.02.047
更新日期:2005-10-01 00:00:00
abstract:BACKGROUND/AIMS:Primary and secondary liver tumours are a common clinical problem, with a poor prognosis in most cases. Surgical resection offers the best outcome, but is only appropriate for the minority. Thermal ablation techniques have been described, but the lack of an optimal means of monitoring has limited their ...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/s0168-8278(99)80234-7
更新日期:1999-08-01 00:00:00
abstract::The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex ...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2014.08.014
更新日期:2014-11-01 00:00:00
abstract:BACKGROUND/AIMS:Alamifovir is a purine nucleotide analogue prodrug that shows potent activity against wild type and lamivudine resistant hepatitis B virus in preclinical studies. The aim of this study was to assess the safety and potential antiviral effects of alamifovir in humans. METHODS:A randomised, placebo contro...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/j.jhep.2004.07.028
更新日期:2004-11-01 00:00:00
abstract:BACKGROUND/AIMS:Platelet function abnormalities contribute to the hemostatic defect in patients with cirrhosis. In this study we evaluated the occurrence of in vivo platelet activation as a possible mechanism of defective platelet aggregation in patients with cirrhosis. METHODS:Nine patients with severe (Child B-C) ci...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(96)80164-4
更新日期:1996-04-01 00:00:00
abstract::Hepatic fibrosis represents an important stage in the progression of chronic liver disease to cirrhosis. In the present paper we have investigated whether capsaicin-sensitive neuropeptide-containing sensory neurons may participate in the development of liver fibrosis. The expression of hepatic fibrosis induced by comm...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(90)90212-a
更新日期:1990-11-01 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::Since the early 1990's, hepatitis B immune globulin (HBIG) has been central to the prevention of hepatitis B virus (HBV) recurrence after liver transplantation. When used in combination with oral nucleos(t)ide analogues, HBIG prevents reinfection with HBV in ⩾90% of transplant recipients. While HBIG is highly efficaci...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2011.08.026
更新日期:2012-05-01 00:00:00
abstract::The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2017.10.020
更新日期:2018-03-01 00:00:00
abstract:BACKGROUND/AIM:The aim of this study was to sequence the precore region of HBV isolated from serum and tumorous and non-tumorous liver tissue from patients with hepatocellular carcinoma to identify mutations that might play a role in malignant transformation. METHODS:HBV DNA was extracted from 62 sera, 14 tumorous and...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(98)80212-2
更新日期:1998-01-01 00:00:00
abstract:BACKGROUND & AIMS:Non-selective beta-blockers (NSBBs) are the mainstay of primary prophylaxis of esophageal variceal bleeding in patients with liver cirrhosis. We investigated whether non-invasive markers of portal hypertension correlate with hemodynamic responses to NSBBs in cirrhotic patients with esophageal varices....
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.10.018
更新日期:2019-03-01 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::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:Hepatic stellate cells (HSCs) are perisinusoidal pericytes which have receptors for vasoactive factors, such as endothelin-1, which can regulate cell contractility in an autocrine manner. It is unknown whether human HSCs have receptors for and are able to synthesize the vasodilator peptide adrenomedulli...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(00)00016-7
更新日期:2001-02-01 00:00:00
abstract:BACKGROUND/AIMS:The aim of this study was to determine the prevalence and clinical significance of hepatitis C virus (HCV) infection in patients with the antiphospholipid syndrome (APS). METHODS:A series of 88 consecutive patients (78 female and 10 male), with a mean age of 39 years (range 15-79), was prospectively st...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80127-5
更新日期:1999-05-01 00:00:00