Activation of hepatocyte cannabinoid receptor-1 (CB
1
R) by hepatic stellate cell (HSC)-derived 2-arachidonoylglycerol (2-AG) drives
de novo
lipogenesis in alcoholic liver disease (ALD). How alcohol ...stimulates 2-AG production in HSCs is unknown. Here, we report that chronic alcohol consumption induced hepatic cysteine deficiency and subsequent glutathione depletion by impaired transsulfuration pathway. A compensatory increase in hepatic cystine-glutamate antiporter xCT boosted extracellular glutamate levels coupled to cystine uptake both in mice and in patients with ALD. Alcohol also induced the selective expression of metabotropic glutamate receptor-5 (mGluR5) in HSCs where mGluR5 activation stimulated 2-AG production. Consistently, genetic or pharmacologic inhibition of mGluR5 or xCT attenuated alcoholic steatosis in mice via suppression of 2-AG production and subsequent CB
1
R-mediated
de novo
lipogenesis. We conclude that a bidirectional signaling operates at a metabolic synapse between hepatocytes and HSCs through xCT-mediated glutamate/mGluR5 signaling to produce 2-AG, which induces CB
1
R-mediated alcoholic steatosis.
Choi et al. show that chronic alcohol consumption induces CYP2E1-mediated ROS production by hepatocytes, which is compensated by GSH generation through xCT-mediated uptake of cystine. The parallel release of glutamate stimulates mGluR5 on hepatic stellate cells (HSCs) to produce 2-AG which, in turn, activates CB-iR on neighboring hepatocytes to induce
de novo
lipogenesis.
Purpose
Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study ...aimed to evaluate the performance of
18
F–fluorodeoxyglucose positron emission tomography (
18
F–FDG PET) for predicting tumour progression during sorafenib treatment.
Methods
We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing
18
F–FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured.
Results
Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR ≥ 2.9 (
n
= 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (
n
= 18) had median OS of 12.2 months (
P
< 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR ≥ 2.9 (hazard ratio HR = 6.318,
P
= 0.002) and Child-Pugh class B (HR = 4.316,
P
= 0.044) were poor prognostic factors for OS, and a TLR ≥ 2.9 (HR = 2.911,
P
= 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis.
Conclusion
Pretreatment tumour metabolic activity assessed by
18
F–FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment.
Background: Recently, beneficial roles of ginsenoside F2 (GF2), a minor constituent of Panax ginseng, have been demonstrated in diverse inflammatory diseases. However, its roles in alcoholic liver ...inflammation and injury have not been clearly understood. Here, we investigated the underlying mechanism by which GF2 ameliorated alcoholic liver injury. Methods: To induce alcoholic liver injury, C57BL/6J wild type (WT) or interleukin (IL)-10 knockout (KO) mice were orally administered with ethanol (3 g/kg) or ethanol-containing GF2 (50 mg/kg) for 2 wk. Liver injury and infiltration of macrophages and neutrophils were evaluated by serum biochemistry and immunohistochemistry, respectively. The changes of hepatic immune cells were assessed by flow cytometry and polymerase chain reaction analysis. In vitro differentiation of naïve T cells was performed. Results: GF2 treatment significantly attenuated alcoholic liver injury, in which infiltrations of inflammatory macrophages and neutrophils were decreased. Moreover, the frequencies of Foxp3+ regulatory T cells (Tregs) increased but IL-17-producing T (Th17) cells decreased in GF2-treated mice compared to controls. Furthermore, the mRNA expression of IL-10 and Foxp3 was significantly increased, whereas IL-17 mRNA expression was suppressed in GF2-treated mice. However, these beneficial roles of GF2 were not observed in GF2-treated IL-10 KO mice, suggesting a critical role of IL-10. Similarly, GF2 treatment suppressed differentiation of naïve T cells into Th17 cells by inhibiting RORgt expression and stimulating Foxp3 expression. Conclusion: The present study suggests that GF2 treatment attenuates alcoholic liver injury by increasing IL-10 expression and Tregs and decreasing IL-17 expression and Th17 cells.
PURPOSEThe endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established ...different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis. However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects. Thus, a more delicate and detailed elucidation of the mechanism linking the endocannabinoid system and ALD may be of paramount significance in efforts to apply the system to the treatment of ALD. SEARCH METHODSThree electronic databases (PubMed, MEDLINE, and Cochrane Library) were used for literature search from November 1988 to April 2021. Major keywords used for literature searches were "cannabinoid," "cannabinoid receptor," "ALD," "steatosis," and "fibrosis." SEARCH RESULTSAccording to the inclusion and exclusion criteria, the authors selected 47 eligible full-text articles out of 2,691 searched initially. Studies in the past 3 decades revealed the opposite effects of cannabinoid receptors CB1R and CB2R on steatosis, inflammation, and fibrosis in ALD. DISCUSSION AND CONCLUSIONSThis review summarizes the endocannabinoid signaling in the general physiology of the liver, the pathogenesis of ALD, and some of the potential therapeutic implications of cannabinoid-based treatments for ALD.
Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study aimed ...to evaluate the performance of
F-fluorodeoxyglucose positron emission tomography (
F-FDG PET) for predicting tumour progression during sorafenib treatment.
We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing
F-FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured.
Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR ≥ 2.9 (n = 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (n = 18) had median OS of 12.2 months (P < 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR ≥ 2.9 (hazard ratio HR = 6.318, P = 0.002) and Child-Pugh class B (HR = 4.316, P = 0.044) were poor prognostic factors for OS, and a TLR ≥ 2.9 (HR = 2.911, P = 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis.
Pretreatment tumour metabolic activity assessed by
F-FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment.
Hepatogastric fistula following a pyogenic liver abscess is extremely rare, and only a handful of cases have been reported. An 88-year-old female presented with generalized weakness, fever and ...chills. An abdominal computed tomography scan revealed a 5cm-sized hypodense lesion with internal septa in the left lateral section of the liver. Due to initial suspicion of early liver abscess, she was treated with empirical intravenous antibiotics. Initially, aspiration or drainage of the liver abscess was not performed due to immature lesion characteristics. An ultrasonography-guided percutaneous drainage of the liver abscess was performed 17 days after hospitalization due to a more mature lesion appearance on follow-up imaging. On tubography, contrast media leakage through the fistulous tract was visualized. Surgical management was performed, and she was discharged 2 weeks after surgery. (Clin Mol Hepatol 2017;23:87-90)
Background/Aims: The treatments and outcomes of hepatocellular carcinoma (HCC) with bile duct invasion are not well known. We aimed to confirm the safety of transarterial chemolipiodolization (TACL) ...and identify prognostic factors for patients with bile duct invasion treated with TACL.
Methods: Fifty patients with central bile duct invasion treated with TACL between 2005 and 2017 were enrolled. Patients were divided into three groups: hyperbilirubinemia (total bilirubin≥2.5 mg/dL) with pre-TACL biliary drainage, hyperbilirubinemia without biliary drainage, and without hyperbilirubinemia. Tumor response to TACL, survival outcomes, length of hospitalization, adverse events using Common Terminology Criteria for Adverse Events (CTCAE), and factors affecting overall survival were compared.
Results: TACL-induced changes of mean CTCAE grades for albumin, alanine aminotransferase, creatinine, prothrombin time, and platelet were not significantly different among patients with or without initial hyperbilirubinemia. Serum bilirubin level was not significantly changed after TACL in all the three groups. Overall survival was not significantly different among the three groups (P=0.097). On multivariate analysis, alpha-fetoprotein <400 ng/dL (hazard ratio HR=0.477, P=0.048) and highest total bilirubin level of <2.5 mg/dL within one month after TACL (HR=0.335, P=0.004) were significantly associated with longer survival.
Conclusions: TACL was a safe treatment for HCC patients with central bile duct invasion, irrespective of the presence of initial hyperbilirubinemia. KCI Citation Count: 1
Background/Aims: The treatments and outcomes of hepatocellular carcinoma (HCC) with bile duct invasion are not well known. We aimed to confirm the safety of transarterial chemolipiodolization (TACL) ...and identify prognostic factors for patients with bile duct invasion treated with TACL.
Methods: Fifty patients with central bile duct invasion treated with TACL between 2005 and 2017 were enrolled. Patients were divided into three groups: hyperbilirubinemia (total bilirubin ≥2.5 mg/dL) with pre-TACL biliary drainage, hyperbilirubinemia without biliary drainage, and without hyperbilirubinemia. Tumor response to TACL, survival outcomes, length of hospitalization, adverse events using Common Terminology Criteria for Adverse Events (CTCAE), and factors affecting overall survival were compared.
Results: TACL-induced changes of mean CTCAE grades for albumin, alanine aminotransferase, creatinine, prothrombin time, and platelet were not significantly different among patients with or without initial hyperbilirubinemia. Serum bilirubin level was not significantly changed after TACL in all the three groups. Overall survival was not significantly different among the three groups (P=0.097). On multivariate analysis, alpha-fetoprotein <400 ng/dL (hazard ratio HR=0.477, P=0.048) and highest total bilirubin level of <2.5 mg/dL within one month after TACL (HR=0.335, P=0.004) were significantly associated with longer survival.
Conclusions: TACL was a safe treatment for HCC patients with central bile duct invasion, irrespective of the presence of initial hyperbilirubinemia. (J Liver Cancer 2018;18:121-129)
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