FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation

AIM: To examine the effect of farnesoid X receptor (FXR) activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanism.

Prediction of hepatic inflammation in chronic hepatitis B patients with a random forest-backward feature elimination algorithm

BACKGROUND Persistent liver inflammatory damage is the main risk factor for developing liver fibrosis,cirrhosis,and even hepatocellular carcinoma in chronic hepatitis B(CHB)patients.Thus,accurate prediction of the degree of liver inflammation is a high priority and a growing medical need.AIM To build an effective and robust non-invasive model for predicting hepatitis Brelated hepatic inflammation.METHODS A total of 650 treatment-naïve CHB(402 HBeAg-positive and 248 HBeAgnegative)patients who underwent liver biopsy were enrolled in this study.Histological inflammation grading was assessed by the Ishak scoring system.Serum quantitative hepatitis B core antibody(qAnti-HBc)levels and 21 immunerelated inflammatory factors were measured quantitatively using a chemiluminescent microparticle immunoassay.A backward feature elimination(BFE)algorithm utilizing random forest(RF)was used to select optional features and construct a combined model.The diagnostic abilities of the model or variables were evaluated based on the estimated area under the receiver operating characteristics curve(AUROC)and compared using the DeLong test.RESULTS Four features were selected to predict moderate-to-severe inflammation in CHB patients using the RF-BFE method.These predictive features included qAnti-HBc,ALT,AST,and CXCL11.Spearman’s correlation analysis indicated that serum qAnti-HBc,ALT,AST,and CXCL11 levels were positively correlated with the histology activity index(HAI)score.These selected features were incorporated into the model to establish a novel model named I-3A index.The AUROC[0.822;95%confidence interval(CI):0.790-0.851]of the I-3A index was significantly increased compared with qAnti-HBc alone(0.760,95%CI:0.724-0.792,P<0.0001)in all CHB patients.The use of an I-3A index cutoff value of 0.41 produced a sensitivity of 69.17%,specificity of 81.44%,and accuracy of 73.8%.Additionally,the I-3A index showed significantly improved diagnostic performance for predicting moderate-to-severe inflammation in HBeAg-positive and HBeAgnegative CHB patients(0.829,95%CI:0.789-0.865 and 0.810,95%CI:0.755-0.857,respectively).CONCLUSION The selected features of the I-3A index constructed using the RF-BFE algorithm can effectively predict moderate-to-severe liver inflammation in CHB patients.

On the Impairment of Stress-Induced Changes in Triglyceride Levels via a Sub-Toxic Dose of Unmethylated Cytidine Phosphate Guanosine Oligodinucleotide (a Toll-Like Receptor 9 Ligand)

Changes in lipid metabolism have been implicated in protection against infectious diseases. In the first experiment of this study, we measured clinical lipid parameters in a murine model where the unmethylated cytidine phosphate guanosine (CpG) oligodinucleotide (ODN1826), a Toll-like receptor 9 (TLR9) agonist was administered in combination with D-galactosamine (GalN) that caused relatively liver-specific inflammation and toxicity. In the control mice group injected with phosphate-buffered saline (PBS) (acute psychological stress model associated with blood sampling), the serum triglyceride (TG) levels showed a rapid decrease followed by a rebound at 24 h as we have recently reported. However, such a TG rebound was impaired in the CpG/GalN- and solely CpG-treated groups of mice despite an absence of liver injury based on serum alanine aminotransferase levels in the latter group. Thus, the stress-associated serum TG rebound was abrogated by the injection of a sub-hepatotoxic CpG dose. In the second experiment, we simply measured the hepatic CD36 and SACRB1 (the gene for scavenger receptor B1 (SR-B1)) transcripts after the i.p. administration of PBS, CpG or CpG/GalN. There was a remarkable elevation of hepatic CD36 transcript expression in both the CpG- and CpG/GalN-treated mice at 8 h post-CpG injection whereas the increase in the PBS-treated mice was slower than the former two groups, suggesting that hepatic CD36 transcript expression is more pronounced in the combined stress models than under psychological stress alone. The individual mice data showed that the increase in CD36 expression was accompanied by a reduction in SCARB1 mRNA, showing reciprocal regulation between these two genes. Together with our previously reported findings, these data suggest that, in a murine model combining psychological stress with TLR-triggered hepatic inflammation, the psychological stress facilitates liver uptake of plasma TG (and its components fatty acids), but the subsequent re-esterification and/or release of TG-rich lipoproteins from the liver is impaired due to the concomitant TLR-signaling. We hypothesize that lipid metabolism during acute stress shifts toward an elevated hepatic uptake of lipids due to concomitant TLR signaling, facilitating the clearance of bacterial lipids by the liver.

Hydroxycitric acid does not promote inflammation or liver toxicity

Garcinia cambogia extract(GC)with its active component consisting of hydroxycitric acid(HCA)is widely utilized for weight loss.Various HCA salts are available,including calcium,magnesium,potassium and mixtures of these.Experimentally,these salts exhibit different properties with some,but not all,improving glucose tolerance and blood pressure.Recently,obesity-prone C57BL/6J mice were fed a high-fat diet(HFD,45 kcal%fat)with or without GC(1%,w/w)for 16 wk.The active arm reduced visceral fat,adipocyte size and serum glucose,yet purportedly also exhibited hepatic collagen accumulation,lipid peroxidation and increased mRNA levels of genes related to oxidative stress.The latter findings are at odds with a large body of animal and human studies that have been conducted on the safety and efficacy of HCA.This literature shows HCA to be protective against the liver toxicity associated with ethanol and dexamethasone administration,and to maintain serum aspartate aminotransferase,alanine aminotransferase and alkaline phosphatase at near normal levels.In both animal and clinical literature,elevated intakes of HCA per se have not led to signs of inflammation or hepatotoxicity.The compound has been found to reduce markers of inflammation in brain,intestines,kidney and serum.

Silybin and the liver: From basic research to clinical practice

Herbal products are increasingly used, mainly in chronic liver disease. Extracts of milk thistle, Silymarin and silybin, are the most prescribed natural compounds, with different indications, but with no definitive results in terms of clinical efficacy. This review analyzes the available studies on the effects of the purified product silybin, both as a free and a conjugated molecule, on liver cells or on experimentally induced liver damage, and in patients with liver disease. We searched PUBMED for articles pertaining to the in vitro and in vivo effects of silybin, its antifibrotic, anti-inflammatory, and antioxidant properties, as well as its metabolic effects, combined with the authors’ own knowledge of the literature. Results indicate that the bioavailability of silybin phytosome is higher than that of silymarin and is less influenced by liver damage; silybin does not show significant interactions with other drugs and at doses < 10 g/d has no significant side effects. Experimental studies have clearly demonstrated the antifibrotic, antioxidant and metabolic effects of silybin; previous human studies were insufficient for confirming the clinical efficacy in chronic liver disease, while ongoing clinical trials are promising. On the basis of literature data, silybin seems a promising drug for chronic liver disease.

Impact of liver diseases on the development of type 2 diabetes mellitus

The prevalence of type 2 diabetes mellitus （T2DM） is higher in patients who have liver diseases such as nonalcoholic fatty liver disease, chronic viral hepatitis, hemochromatosis, alcoholic liver disease and cirrhosis. It is suggested that there is a pathogenic link between the presence of T2DM and the severity of liver injury. However, evidence related to the impact of hepatic inflammation on the development of T2DM has not yet emerged. This article provides an overview of the evidence for an increased prevalence of diabetes in a range of liver diseases, the impact of liver diseases on insulin resistance and 13 cell dysfunction, and the potential mechanisms whereby coexistent liver diseases exacerbate the development of T2DM.

Persea americana attenuates inflammatory response associated with hyperlipidemia in ovariectomized and irradiated rats by regulating MMP-3/TIMP-1 levels

Objective:To explore the effect of Persea americana supplementation on inflammation,oxidative stress,and lipid profiles in ovariectomized rats fed with a high-fat diet and exposed to radiation.Methods:The control group was sham operated,while groups 2-5 were ovariectomized and fed a high-fat diet.Groups 4 and 5 were exposed toγ-radiation(1 Gy/week for 5 weeks)after ovariectomy.Groups 3 and 5 were treated with 1 mL/250 g/day of Persea americana for one month.Serum levels of estrogen,alanine aminotransferase,aspartate aminotransferase,cholesterol,triglycerides and lipoproteins were measured.Additionally,hepatic oxidative stress,inflammatory and fibrogenic markers were evaluated.Results:Persea americana treatment reduced the oxidative stress markers as well as the levels of triglyceride,total cholesterol,and low-density lipoprotein cholesterol,which in turn lowered hepatic fat accumulation.Moreover,it suppressed hepatic inflammatory mediators(interleukin-6,tumor necrosis factor-α,and C-reactive protein)and downregulated pro-fibrogenic markers(transforming growth factor-βand tissue inhibitor of metalloproteinase-1).Conclusions:Persea americana provides protection against ovariectomy,and gamma radiation-mediated hepatic inflammation not only through its antioxidant,anti-inflammatory,lipid-lowering effect but also by modulating the fibrogenic markers.

Anti-inflammatory and anti-oxidant effects of aloe vera in rats with non-alcoholic steatohepatitis

BACKGROUND Aloe vera exerts several biological activities,such as,anti-inflammatory,antioxidant,and antimicrobial effects.It was recently shown to reduce insulin resistance and triglyceride level.We hypothesized that aloe vera would have beneficial effects in alleviating non-alcoholic steatohepatitis(NASH)in rats.AIM To examine the therapeutic effects of aloe vera in NASH rats.METHODS All rats were randomly divided into 3 groups(n=6 in each group).Rats in the control group were fed ad libitum with a standard diet for 8 wk.Rats in the NASH group were fed ad libitum with a high-fat high-fructose diet(HFHFD)for 8 wk.Rats in the aloe vera group were fed ad libitum with a HFHFD and aloe vera in dimethylsulfoxide(50 mg/kg)by gavage daily for 8 wk.Liver samples were collected at the end of the treatment period.RESULTS Hepatic malondialdehyde(MDA)levels increased significantly in the NASH group as compared with the control group(377±77 nmol/mg vs 129±51 nmol/mg protein,respectively,P<0.001).Glutathione(GSH)levels were significantly lower in the NASH group than the control group(9±2 nmol/mg vs 24±8 nmol/mg protein,respectively,P=0.001).The expression of interleukin-18 (IL-18), nuclear factor-kappa β, and caspase-3 increased, while peroxisomeproliferator-activated receptor gamma decreased in the NASH group comparedwith the controls. Following aloe vera administration, MDA levels decreased (199± 35 nmol/mg protein) and GSH increased (18 ± 4 nmol/mg protein) markedly.Steatosis, hepatocyte ballooning, lobular inflammation and increased hepatocyteapoptosis were observed in the NASH group. Aloe vera treatment attenuatedthese changes in liver histology.CONCLUSIONAloe vera attenuated oxidative stress, hepatic inflammation and hepatocyteapoptosis, thus improving liver pathology in rats with NASH.

Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF-αsignaling

Background Hepatic inflammation is the major risk factor of hepatocellular carcinoma(HCC).However,the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood.This study was designed to investigate the role of ETS translocation variant 4(ETV4)in linking hepatic inflammation to HCC.Methods Quantitative real-time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines.RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4.Hepatocyte-specific ETV4-knockout(ETV4fl/fl,alb-cre)and transgenic(ETV4Hep-TG)mice and diethylnitrosamine-carbon tetrachloride(DEN-CCL4)treatment experiments were applied to investigate the function of ETV4 in vivo.The Cancer Genome Atlas(TCGA)database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor-alpha(TNF-α)and mitogen-activated protein kinase 11(MAPK11).Results We revealed that ETV4 was highly expressed in HCC.High levels of ETV4 predicted a poor survival rate of HCC patients.Then we identified ETV4 as a transcription activator of TNF-αand MAPK11.ETV4 was positively correlated with TNF-αand MAPK11 in HCC patients.As expected,an increase in hepatic TNF-αsecretion and macrophage accumulation were observed in the livers of ETV4Hep-TG mice.The protein levels of TNF-α,MAPK11,and CD68 were significantly higher in the livers of ETV4Hep-TG mice compared with wild type mice but lower in ETV4fl/fl,alb-cre mice compared with ETV4fl/fl mice as treated with DEN-CCL4,indicating that ETV4 functioned as a driver of TNF-α/MAPK11 expression and macrophage accumulation during hepatic inflammation.Hepatocyte-specific knockout of ETV4 significantly prevented development of DEN-CCL4-induced HCC,while transgenic expression of ETV4 promoted growth of HCC.Conclusions ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF-αand MAPK11.Both the ETV4/TNF-αand ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC.ETV4+TNF-αwere potential prognostic markers for HCC patients.

Acute-on-chronic liver failure：recent update

Acute on chronic liver failure（ACLF） was first described in 1995 as a clinical syndrome distinct to classic acute decompensation.Characterized by complications of decompensation,ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between45%and 90%.Despite the clinical relevance of the condition,it still remains largely undefined with continued disagreement regarding its precise etiological factors,clinical course,prognostic criteria and management pathways.It is concerning that,despite our relative lack of understanding of the condition,the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%.This paper highlights our current understanding of ACLF,including its etiology,diagnostic and prognostic criteria and pathophysiology.It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates.The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters,while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.

Promotion of nonalcoholic steatohepatitis by RNA N^(6)-methyladenosine reader IGF2BP2 in mice

Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the present study,through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis,we identified IGF2BP2,an N6-methyladenosine modification reader,as a key regulator that promotes NASH progression in mice.Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis,inflammation,and fibrosis in mice,at least in part,by increasing Tab2 mRNA stability.Besides,hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers.Of potential clinical significance,IGF2BP2 expression is significantly upregulated in the livers of NASH patients.Moreover,knockdown of IGF2BP2 substantially alleviated liver injury,inflammation,and fibrosis in diet-induced NASH mice.Taken together,our findings reveal an important role of IGF2BP2 in NASH,which may provide a new therapeutic target for the treatment of NASH.