Summary It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions ...highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an increase in the prevalence of obesity and the metabolic syndrome promotes pathophysiological changes that cause non-alcoholic fatty liver disease (NAFLD). NAFLD increases the susceptibility of the liver to acute liver injury and may lead to cirrhosis and hepatocellular cancer. Alterations in insulin response, β- oxidation, lipid storage and transport, autophagy and an imbalance in chemokines and nuclear receptor signaling are held accountable for these changes. Furthermore, recent studies revealed a role for lipid accumulation in inflammation and ER stress in the clinical context of liver regeneration and hepatic carcinogenesis. This review focuses on novel findings related to nuclear receptor signaling – including the vitamin D receptor and the liver receptor homolog 1 – in hepatic lipid and glucose uptake, storage and metabolism in the clinical context of NAFLD, liver regeneration, and cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In chronic liver disease, hepatic stellate cells (HSCs) are activated, highly proliferative and produce excessive amounts of extracellular matrix, leading to liver fibrosis. Elevated levels of toxic ...reactive oxygen species (ROS) produced during chronic liver injury have been implicated in this activation process. Therefore, activated hepatic stellate cells need to harbor highly effective anti-oxidants to protect against the toxic effects of ROS.
To investigate the protective mechanisms of activated HSCs against ROS-induced toxicity.
Culture-activated rat HSCs were exposed to hydrogen peroxide. Necrosis and apoptosis were determined by Sytox Green or acridine orange staining, respectively. The hydrogen peroxide detoxifying enzymes catalase and glutathione-peroxidase (GPx) were inhibited using 3-amino-1,2,4-triazole and mercaptosuccinic acid, respectively. The anti-oxidant glutathione was depleted by L-buthionine-sulfoximine and repleted with the GSH-analogue GSH-monoethylester (GSH-MEE).
Upon activation, HSCs increase their cellular glutathione content and GPx expression, while MnSOD (both at mRNA and protein level) and catalase (at the protein level, but not at the mRNA level) decreased. Hydrogen peroxide did not induce cell death in activated HSCs. Glutathione depletion increased the sensitivity of HSCs to hydrogen peroxide, resulting in 35% and 75% necrotic cells at 0.2 and 1mmol/L hydrogen peroxide, respectively. The sensitizing effect was abolished by GSH-MEE. Inhibition of catalase or GPx significantly increased hydrogen peroxide-induced apoptosis, which was not reversed by GSH-MEE.
Activated HSCs have increased ROS-detoxifying capacity compared to quiescent HSCs. Glutathione levels increase during HSC activation and protect against ROS-induced necrosis, whereas hydrogen peroxide-detoxifying enzymes protect against apoptotic cell death.
•Glutathione does not alter hepatic stellate cell activation or morphology.•Glutathione protects stellate cells against ROS-induced necrosis.•Glutathione peroxidase and catalase protect HSCs against ROS-induced apoptosis.•GAPDH and beta-actin are inappropriate proteins to normalize Western blot data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)‐induced ...lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high‐affinity Na+/taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha‐hydroxylase (CYP7A1) were significantly up‐regulated in obese patients and hepatoma cells exposed to FFA. Up‐regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. Conclusion: BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP‐mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early treatment with FXR ligands and/or adiponectin‐receptor agonists might prevent NASH. (HEPATOLOGY 2013;57:1394–1406)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background & Aims Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that ...Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling. Methods Mice with either hepatocyte-specific depletion of KLF6 (‘ΔHepKlf6’) or global KLF6 heterozygosity ( Klf6 +/−) were fed a high fat diet (HFD) or chow for 8 or 16 weeks. Glucose and insulin tolerance tests were performed to assess insulin sensitivity. Overexpression and knockdown of KLF6 in cultured cells enabled the elucidation of underlying mechanisms. In liver samples from a cohort of 28 NAFLD patients, the expression of KLF6-related target genes was quantified. Results Mice with global- or hepatocyte-depletion of KLF6 have reduced body fat content and improved glucose and insulin tolerance, and are protected from HFD-induced steatosis. In hepatocytes, KLF6 deficiency reduces PPARα-regulated genes ( Trb3 , Pepck ) with diminished PPARα protein but no change in Pparα mRNA, which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARα. In NAFLD patients with advanced disease and inflammation, the expression of miRNA 10b is significantly downregulated, while PEPCK mRNA is upregulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. Conclusions KLF6 increases PPARα activity, whereas KLF6 loss leads to PPARα repression and attenuation of lipid and glucose abnormalities associated with a high fat diet. The findings establish KLF6 as a novel regulator of hepatic glucose and lipid metabolism in fatty liver.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Targeted therapies have drastically changed the management of metastatic melanoma and have shown encouraging results on tumour progression but are also known for their high rates of adverse ...reactions. In general, targeted therapies are contraindicated during pregnancy due to concerns about teratogenesis. For the BRAF V600 inhibitor vemurafenib, the available literature about the effects on human pregnancy is limited to a single case report. In patients with metastatic melanoma that wish to continue their pregnancy, targeted therapies like vemurafenib offer the only possibility of improving maternal outcome. In this article, we report on a pregnant woman with metastatic melanoma who was treated with vemurafenib during pregnancy and experienced a fatal adverse reaction.
The polymorphism, KLF6‐IVS1‐27A, in the Krüppel‐like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression ...of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6‐IVS1‐27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity. KLF6‐IVS1‐27Gwt (i.e., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver‐specific Gck promoter and activates a GCK promoter‐reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes Gck expression was reduced and stable transfection of Klf6 led to up‐regulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat‐laden hepatocytes. In contrast to full‐length KLF6, splice variant KLF6‐SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity. Conclusion: KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6‐IVS1‐27A polymorphism, which generates more KLF6‐SV1, combats this, lowering hepatic insulin resistance and blood glucose. (HEPATOLOGY 2011)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Purpose
Deep neuromuscular blockade (NMB) can improve surgical conditions and possibly pain after low-risk laparoscopic surgery. We hypothesized that targeting a deep level of NMB by a continuous ...compared with an on-demand infusion of rocuronium could improve surgical conditions in patients undergoing thoraco-laparoscopic esophagectomy.
Methods
In this single-centre, randomized-controlled, double-blind trial, patients received either a continuous infusion of rocuronium 0.6 mg·kg
−1
·hr
−1
(intervention) or NaCl 0.9% (control). Both surgeon and anesthesiologist were blinded to group assignment and the train-of-four measurements. Open-label rocuronium was given if requested (i.e., on-demand) by the surgeon. At the end of surgery, sugammadex was given if necessary to reverse the NMB. The primary outcome was the quality of surgical conditions during the abdominal phase of the operation as measured by the surgical rating scale (SRS). Secondary outcomes included the thoracic SRS, number of on-demand boluses, intraoperative surgical events, pain scores (up to 12 hr postoperatively), and duration of surgery.
Results
The median interquartile range abdominal SRS was not different between the intervention (4 4–5) and control (4 4–5) groups (median difference, 0; 95% confidence interval, 0 to 0;
P
= 0.45). The thoracic SRS was 4 4–4 in both groups (
P
= 0.23). The median number of rocuronium bolus requests was higher in the control group compared with the intervention group (3 3–6
vs
1 0–2, respectively;
P
< 0.01). There were no between-group differences in intraoperative surgical events (
P
= 0.05), pain scores (overall
P
> 0.05), or duration of surgery (
P
= 0.95).
Conclusions
Continuous rocuronium infusion did not improve surgical conditions when boluses of rocuronium were available on-demand. No major benefits in other outcomes were seen.
Trial registration
EUDRACT (2014-002147-18); registered 19 May, 2014 and clinicaltrials.gov (NCT02320734); registered 18 December, 2014.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Genomics and proteomics have become increasingly important in biomedical science in the past decade, as they provide an opportunity for hypothesis-free experiments that can yield major insights not ...previously foreseen when scientific and clinical questions are based only on hypothesis-driven approaches. Use of these tools, therefore, opens new avenues for uncovering physiological and pathological pathways. Liver fibrosis is a complex disease provoked by a range of chronic injuries to the liver, among which are viral hepatitis, (non-) alcoholic steatohepatitis and autoimmune disorders. Some chronic liver patients will never develop fibrosis or cirrhosis, whereas others rapidly progress towards cirrhosis in a few years. This variety can be caused by disease-related factors (for example, viral genotype) or host-factors (genetic/epigenetic). It is vital to establish accurate tools to identify those patients at highest risk for disease severity or progression in order to determine who are in need of immediate therapies. Moreover, there is an urgent imperative to identify non-invasive markers that can accurately distinguish mild and intermediate stages of fibrosis. Ideally, biomarkers can be used to predict disease progression and treatment response, but these studies will take many years due to the requirement for lengthy follow-up periods to assess outcomes. Current genomic and proteomic research provides many candidate biomarkers, but independent validation of these biomarkers is lacking, and reproducibility is still a key concern. Thus, great opportunities and challenges lie ahead in the field of genomics and proteomics, which, if successful, could transform the diagnosis and treatment of chronic fibrosing liver diseases.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Most chronic liver diseases are accompanied by oxidative stress, which may induce apoptosis in hepatocytes and liver injury. Oxidative stress induces heme oxygenase-1 (HO-1) expression. This ...stress-responsive cytoprotective protein is responsible for heme degradation into carbon monoxide (CO), free iron, and biliverdin. CO is an important intracellular messenger; however, the exact mechanisms responsible for its cytoprotective effect are not yet elucidated. Thus, we investigated whether HO-1 and CO protect primary hepatocytes against oxidative-stress-induced apoptosis. In vivo, bile duct ligation was used as model of chronic liver disease. In vitro, primary hepatocytes were exposed to the superoxide anion donor menadione in a normal and in a CO– containing atmosphere. Apoptosis was determined by measuring caspase-9, -6, -3 activity and poly(ADP-ribose) polymerase cleavage, and necrosis was determined by Sytox green staining. The results showed that (1) HO-1 is induced in chronic cholestatic liver disease, (2) superoxide anions time- and dose-dependently induce HO-1 activity, (3) HO-1 overexpression inhibits superoxide-anions-induced apoptosis, and (4) CO blocks superoxide-anions-induced JNK phosphorylation and caspase-9, -6, -3 activation and abolishes apoptosis but does not increase necrosis. We conclude that HO-1 and CO protect primary hepatocytes against superoxide-anions-induced apoptosis partially via inhibition of JNK activity. CO could represent an important candidate for the treatment of liver diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background: In chronic liver injury, hepatic stellate cells (HSCs) proliferate and produce excessive amounts of connective tissue causing liver fibrosis and cirrhosis. Oxidative stress has been ...implicated as a driving force of HSC activation and proliferation, although contradictory results have been described.
Aim: To determine the effects of oxidative stress on activated HSC proliferation, survival and signalling pathways.
Methods: Serum‐starved culture‐activated rat HSCs were exposed to the superoxide anion donor menadione (5–25 μmol/L) or hydrogen peroxide (0.2–5 mmol/L). Haem oxygenase‐1 mRNA expression, glutathione status, cell death, phosphorylation of mitogen‐activated protein (MAP) kinases and proliferation were investigated.
Results: Menadione induced apoptosis in a dose‐ and time‐dependent, but caspase‐independent manner. Hydrogen peroxide induced necrosis only at extremely high concentrations. Both menadione and hydrogen peroxide activated Jun N‐terminal kinase (JNK) and p38. Hydrogen peroxide also activated extracellular signal‐regulated protein. Menadione, but not hydrogen peroxide, reduced cellular glutathione levels. Inhibition of JNK or supplementation of glutathione reduced menadione‐induced apoptosis. Non‐toxic concentrations of menadione or hydrogen peroxide inhibited platelet‐derived growth factor‐ or/and serum‐induced proliferation.
Conclusion: Reactive oxygen species (ROS) inhibit HSC proliferation and promote HSC cell death in vitro. Different ROS induce different modes of cell death. Superoxide anion‐induced HSC apoptosis is dependent on JNK activation and glutathione status.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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