The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

Clinical application of serum Golgi protein 73 in patients with chronic liver diseases / 中华肝脏病杂志

Golgi protein 73 (GP73) is a transmembrane protein on the Golgi apparatus and can be cut and released into the blood. In recent years, an increasing number of clinical studies have shown that the elevated serum GP73 level is closely related to liver diseases. And thus GP73 is expected to be used as a new serum marker for assessing progress of chronic liver diseases. Herein, the clinical application of serum GP73 in chronic hepatitis, liver fibrosis, liver cirrhosis and hepatocellular carcinoma with different etiologies was reviewed based on available literatures; and a research outlook in this field is made.

The relationship between serum Golgi protein 73 and both liver inflammation and fibrosis in patients with chronic hepatitis B / 解放军医学杂志

Objective To explore the correlation between serum Golgi protein 73(GP73) and both liver inflammation and fibrosis in patients with chronic hepatitis B(CHB). Methods Altogether 322 patients who underwent liver biopsy were enrolled in this retrospective study, and GP73, ALT, AST, LSM, FIB-4, APRI were analyzed. The relationship between serum GP73 and both liver inflammation and fibrosis was analyzed. Univariate and multivariate logistic regression analysis were used to evaluate the predictive value of GP73 for significant liver injury. Results 322 CHB patients ranged from 18 to 66 years old, including 231 males (71.7%) and 91 females (28.3%), and the median of GP73 was 65.6(35.8-129.6) ng/ml. The serum level of GP73 stepwise increased with increase of liver inflammation grade and liver fibrosis stage, and GP73 was significantly correlated with liver inflammation grade (?=0.536, P<0.001) and fibrosis stage (?=0.536, P<0.001). The degree of liver inflammation or fibrosis at the same stage was analyzed and the results indicated that the serum GP73 levels were significantly correlated with the severity of liver inflammation, while the association between serum GP73 and the stage of liver fibrosis was weaker. In term of the advanced liver inflammation or fibrosis stage, univariate and multivariate analysis revealed that GP73 was simultaneously determined as an independent risk factor for predicting liver inflammation (P<0.001) and fibrosis (P<0.05). Conclusion Serum GP73 is well correlated with liver inflammation and fibrosis in CHB patients, and it might be a new biomarker to predict liver inflammation and fibrosis.

HBsAg Levels Normalized to the Same Hepatic Parenchyma Cell Volume Is Correlated with Pathological Progression but Not HBeAg Status / 中山大学学报(医学科学版)

@#【Objective】To study retrospectively the serum hepatitis B surface antigen（HBsAg）and HBsAg normal⁃ ized to the same hepatic parenchyma cell volume（HPCV），namely，the same hepatic cell quantities，between HBeAg- positive and HBeAg-negative chronic hepatitis B（CHB）.【Methods】A total of 168 CHB patients who had undergone liv⁃ er biopsy and test of serum HBsAg levels due to their disease in the Third Affiliated Hospital of SunYat-sen University were selected as the study subjects. The serum HBsAg levels，as well as HBsAg levels normalized to HPCV（hepatic cell quantities）were compared between HBeAg-positive and HBeAg-negative CHB，respectively.【Results】There was statis⁃ tically significant difference in serum HBsAg levels between HBeAg-positive and HBeAg-negative CHB（P = 0.028）， while there was no statistical difference in HBsAg normalized to HPCV（P = 0.073）. There were no correlations between serum HBsAg and liver inflammation grades（HBeAg-positive：r s = 0.020，P = 0.876 & HBeAg-negative：r s = 0.037，P =0.711）. Similarly，there were no correlations between HBsAg and hepatic fibrosis stages（HBeAg-positive：r s = 0.087， P = 0.488 & HBeAg-negative：r s = 0.144，P = 0.148）. Nevertheless，statistically significant positive correlations were shown between HBsAg normalized to HPCV and liver inflammation grades（HBeAg-positive：r s = 0.309，P = 0.012 & HBeAg-negative：r s = 0.389，P < 0.001）. Similarly，the HBsAg normalized to HPCV and hepatic fibrosis stages were shown to be statistically significantly correlated（HBeAg-positive：r s = 0.490，P < 0.001 & HBeAg-negative：r s = 0.599， P < 0.001）.【Conclusions】Serum HBsAg normalized to HPCV but not HBsAg levels，is correlated with liver inflamma⁃ tion grades as well as hepatic fibrosis stages positively in both HBeAg-positive and HBeAg-negative CHB. But there is no difference in serum HBsAg levels normalized to HPCV between HBeAg-positive and HBeAg-negative CHB.

Establishment of liver IL-6 reporter mouse model by hydrodynamic gene transfection / 军事医学

Objective To construct a mouse model for real-time,noninvasive and specific monitoring of inflammation activation in hepatic tissues.Methods An inflammation reporter gene was targeted to the liver by hydrodynamic gene delivery technology.Bioluminescence imaging was used to detect the firefly luciferase(Fluc) expression in the mouse liver after inflammatory stimulation.Besides,the relevance between the light intensity and inflammation level was also intensively investigated.Results pIL-6-Fluc was successfully delivered to the liver.The hydrodynamic gene delivery could cause a transient liver injury that could return normal in 5 to 7 days.The expression of pIL-6-Fluc could be induced by lipopolysaccharides(LPS) treatment with an about (46.80±13.35) fold increase at the peak value,which was significantly higher than that detected by ELISA [(4.09±0.96)fold].Conclusion An inflammation reporter mouse model is constructed in this study by hydrodynamic gene transfection,allowing noninvasive monitoring of inflammation activation specifically in hepatic tissues.The reporter model is capable of monitoring inflammation activation with a sensitivity higher than that of ELISA.

PXR Mediated Protection against Liver Inflammation by Ginkgolide A in Tetrachloromethane Treated Mice

The pregnane X receptor (PXR), a liver and intestine specific receptor,, has been reported to be related with the repression of inflammation as well as activation of cytochromosome P450 3A (CYP3A) expression. We examined the effect of PXR on tetrachloromethane (CCl4)-induced mouse liver inflammation in this work. Ginkgolide A, one main component of Ginkgo biloba extracts (GBE), activated PXR and enhanced PXR expression level, displayed both significant therapeutic effect and preventive effect against CCl4-induced mouse hepatitis. siRNA-mediated decrease of PXR expression significantly reduced the efficacy of Ginkgolide A in treating CCl4-induced inflammation in mice. Flavonoids, another important components of GBE, were shown anti-inflammatory effect in a different way from Ginkgolide A which might be independent on PXR because flavonoids significantly inhibited CYP3A11 activities in mice. The results indicated that anti-inflammatory effect of PXR might be mediated by enhancing transcription level of IkappaBalpha through binding of IkappaBalpha. Inhibition of NF-kappaB activity by NF-kappaB-specific suppressor IkappaBalpha is one of the potential mechanisms of Ginkgolide A against CCl4-induced liver inflammation.

Effect of Trifolium pratense extract on methionine-choline-deficient diet-induced steatohepatitis in C57BL/6 mice / 中国天然药物

AIM@#The potential of Trifolium pratense (red clover) extract in the prevention of lipid disorder has attracted increasing attention in recent years. In this study, the aim was to determine whether and how red clover extract affected the development of murine diet-induced non-alcoholic steatohepatitis.@*METHODS@#Non-alcoholic steatohepatitis was induced in C57BL/6 mice by feeding mice with a methionine-choline-deficient (MCD) diet. Hematoxylin and eosin staining was used for histological analyses. Real-time PCR was used to analyze the mRNA expression levels.@*RESULTS@#Hepatic steatosis and necroinflammation was observed in MCD diet-fed mice, and this diet-induced steatosis was significantly attenuated, whereas liver inflammation was not significantly attenuated, by red clover extract treatment. Consistent with the results of H&E staining, the MCD diet-induced increase of liver triglycerides and cholesterol levels were significantly reduced by red clover extract treatment. However, with the improvement in hepatic steatosis, mRNA levels of acetyl CoA oxidase, carnitine palmitoyl transferase-1, and liver fatty acid-binding protein, three genes regulated by peroxisome proliferator-activated receptor (PPAR) α, were unaffected.@*CONCLUSION@#Red clover extract alleviated MCD diet-induced hepatic steatosis, but did not ameliorate liver inflammation in C57BL/6 mice, and the improvement in hepatic steatosis was not through activating PPARα.

Eosinophilic Infiltration in the Liver: Unusual Manifestation of Hepatic Segmental Involvement

Eosinophilic infiltration in the liver is not a rare disease and it is usually presented as multiple, small, ill defined, oval or round, low attenuated lesions on portal phase of computed tomography. We reported case of hepatic eosinophilic infiltration in the liver, as an unusual manifestation of segmental involvement.

Roles of Nitric Oxide and Tumor Necrosis Factor in Liver Inloammation Induced by C . parvum and LPS / 대한면역학회지

No abstract available.

Inflammatory Pseudotumor of the Liver: CT Findings

PURPOSE: To evaluate the CT features of inflammatory pseudotumor of the liver with histopathologiccorrelation. MATERIALS AND METHODS: The CT features of 14 cases (ten patients) with pathologically proveninflammatory hepatic pseudotumor were retrospectively analyzed and correlated with resected and biopsy specimens. RESULTS: The size of lesions ranged between 2.0 and 7.0cm (mean, 3.7cm); On unenhanced CT, the masses were seenas ill-defined hypodense lesions, while on contrast-enhanced CT they were heterogeneous and multiseptated, withenhancement of internal septa and peripheral wall (n=10). In four lesions, central low density and peripheralhomogeneous enhancement were seen. On histopathological correlation, the central hypoattenuated area correspondedto chronic inflammalory cell infiltrates with foamy histiocytes, plasmacytes, and lymphocytes, while thehyperattenuated peripheral wall and internal septa represented dense fibrosis. CONCLUSION: In patients in whon CTshows a heterogeneous enhancing mass, inflammatory pseudotumor of the liver should be included in differentialdiagnosis.

Idiopathic Hypereosinophilic Syndrome Involving the Liver: CT Features vs. Peripheral Eosinophilia

PURPOSE: To correlate CT features with peripheral eosinophilia in patients with idiopathic hypereosinophilic syndrome involving the liver. MATERIALS AND METHODS: During the last three years, features of liver involvement in nine of 20 patients with idiopathic hypereosinophilic syndrome were evaluated on CT. The shape and distribution of intrahepatic low densities and the presence of hepatomegaly and/or splenomegaly were reviewed on CT, and the percentage of eosinophils in peripheral blood was also determined. In seven cases, interval change in hepatic lesion and the percentage of eosinophils were reviewed on follow-up examination. RESULTS: On initial CT, varying low-density patterns were seen in the liver in all cases ; hepatomegaly was seen in four cases, and hepatosplenomegaly in two. The percentage of eosinophils was 89% in a case with diffuse patch low densities in the liver, 65-85% in three cases with numerous nodular low density lesions, 12-29% in four cases with multiple (below ten) nodular or small geographic hypodense lesions, and 24% in a case with a single nodular hypodense lesion. On follow-up CT, seven patients showed a decrease in the percentage of eosinophils, and in six, improved intrahepatic low densities were seen. CONCLUSION: On CT, intrahepatic low densities were seen in patients with idiopathic hypereosinophilic syndrome, and these were distributed more extensively when peripheral eosinophilia was more severe. With improvement in peripheral eosinophilia, the low densities also improved.