Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with ß3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, ß3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a ß3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, ß3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.

Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury.

UNLABELLED: In chronic liver injury, liver progenitor cells (LPCs) proliferate in the periportal area, migrate inside the lobule, and undergo further differentiation. This process is associated with extracellular matrix (ECM) remodeling. We analyzed LPC expansion and matrix accumulation in a choline-deficient, ethionine-supplemented (CDE) model of LPC proliferation. After day 3, CDE induced collagen deposits in the periportal area. Expansion of LPCs as assessed by increased number of cytokeratin 19 (CK19)-positive cells was first observed at day 7, while ECM accumulated 10 times more than in controls. Thereafter, LPCs and ECM increased in parallel. Furthermore, ECM not only accumulates prior to the increase in number of LPCs, but is also found in front of LPCs along the porto-venous gradient of lobular invasion. Double immunostaining revealed that LPCs are embedded in ECM at all times. Moreover, LPCs infiltrating the liver parenchyma are chaperoned by alpha-smooth muscle actin (alpha-SMA)-positive cells. Gene expression analyses confirmed these observations. The expression of CK19, alpha-fetoprotein, E-cadherin, and CD49f messenger RNA (mRNA), largely overexpressed by LPCs, significantly increased between day 7 and day 10. By contrast, at day 3 there was a rapid burst in the expression of components of the ECM, collagen I and laminin, as well as in alpha-SMA and connective tissue growth factor expression. CONCLUSION: Our data demonstrate that, in a CDE model, ECM deposition and activation of matrix-producing cells occurred as an initial phase, prior to LPC expansion, and in front of LPCs along the porto-venous gradient of lobular invasion. Those observations may reveal a fundamental role for the established hepatic microenvironment or niche during the process of activation and differentiation of liver progenitor cells.

Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases?

AIMS: This report describes three patients suffering from nodular regenerative hyperplasia (NRH). METHODS: These patients have received six, 16 and 20 cycles of neoadjuvant 5-fluorouracil and oxaliplatin-based chemotherapy before planned extended hepatectomy. Two patients underwent uneventful portal vein embolization to hypertrophy the future remnant liver. RESULTS: At the end of chemotherapy, liver function tests deteriorated and portal hypertension appeared in two patients, including ascites, splenomegaly and oesophageal varices. Liver biopsy was performed through a percutaneous (two patients) or a transjugular approach (one patient) and allowed the diagnosis of NRH, which was considered to be a contraindication for major liver resection in all three patients, associated with extrahepatic disease progression in one patient. All patients died from neoplastic disease progression despite further chemotherapy at 6, 17 and 31 months following the diagnosis of NRH. One patient developed liver failure and ascites at the time of death. CONCLUSIONS: Physicians should be aware of the potential occurrence and therapeutic impact of NRH in patients suffering from CRLM and treated by neoadjuvant 5FU-oxaliplatin-based chemotherapy before major liver surgery.

Role of apoptotic signaling pathway in metabolic disturbances occurring in liver tissue after cryopreservation: Study on rat precision-cut liver slices.

Precision-cut liver slices in culture (PCLS) appears as a useful and widely used model for metabolic studies; the interest to develop an adequate cryopreservation procedure, which would allow maintaining cell integrity upon incubation, is needed to extend its use for human tissues. We have previously shown that cryopreservation of rat PCLS leads to caspase-3 activation and early alterations of their K+ content upon incubation. In this study, we tested the hypothesis that counteracting intracellular K+ loss and/or interfering with cell death signaling pathways could improve the viability of cryopreserved PCLS. PCLS were prepared from male Wistar rat liver and cryopreserved by rapid freezing before incubation. The addition of a caspase inhibitor-Z-DEVD-FMK (2.5 microM)-in the culture medium did not improve viability of cryopreserved PCLS. Incubation of cryopreserved PCLS in a K+ rich medium (135 mM) increased K+ content and avoided caspase-3 activation, but did not improve cell viability. Caspase-3 inhibition, a decrease in cell lysis, and improvement of glycogen content were observed in cryopreserved PCLS after addition of LiCl (100 mM) in the incubation medium. These results indicate that, even if caspase-3 activation is linked to the K+ loss in cryopreserved PCLS, its inhibition does not allow restoring the metabolic capacities. LiCl, acting on a target upstream of caspase-3 inhibition, improves cell viability and allows glycogen accumulation when added in culture medium of cryopreserved PCLS; and could thus be considered as an interesting adjuvant in the culture of cryopreserved PCLS.

131I-Labelled-iodized oil for palliative treatment of hepatocellular carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is growing in western countries. Poor liver status and tumour size make curative options scarce. Palliative treatments such as chemo-embolization are improving survival in selected patients, but side-effects are frequent. There is a need for the validation of alternative treatments. Metabolic radiotherapy using lipiodol labelled with 131I-iodine (I-131-lipiodol) is one of these treatments. OBJECTIVES: To analyse the effect of I-131-lipiodol in a population of advanced HCC patients and to define the potential prognostic factors in this setting. METHODS: A retrospective analysis of the effect of I-131-lipiodol on 29 patients bearing multifocal tumours was performed. An analysis of two subgroups, defined by a Cancer of the Liver Italian Program (CLIP) score of 2 or less (n=20) or greater than 2 (n=9) was performed to assess the prognostic significance of the score in this setting. RESULTS: Overall median survival in the entire study population was 203 days (95% confidence interval 83-322 days). Median survival was significantly better in the group with CLIP scores of 2 or less than in the group with CLIP scores greater than 2 (453 versus 60 days, P< or =0.001). Treatment-related mortality was 6.9% (one interstitial pneumonia and one acute liver failure). CONCLUSION: The survival of patients treated with I-131-lipiodol in this series compared favourably with published data. Stratification according to the CLIP score was useful to predict survival. In particular, patients with portal vein thrombosis should only be considered for I-131-lipiodol if the CLIP score is lower than 2.

Watercress has no Importance for the elimination of ethanol by CYP2E1 inhibition.

Watercress, a cruciferous vegetable, is known to inhibit the metabolism of several CYP2E1 substrates such as paracetamol and chlorzoxazone. Since ethanol and its metabolite, acetaldehyde, are CYP2E1 substrates, the influence of watercress on ethanol and acetaldehyde was investigated in healthy human volunteers. According to a randomized cross-over design, ethanol and acetaldehyde pharmacokinetic parameters were determined in 9 persons at 3 occasions: without watercress and after watercress ingestion preceding ethanol consumption from 1 or 10.5 hr, respectively. Ethanol tmax occurred significantly later when watercress was ingested 1 hr before ethanol ingestion. Likewise, acetaldehyde Cmax was significantly higher whereas acetaldehyde AUCs were increased by watercress but not significantly. All other ethanol and acetaldehyde pharmacokinetic parameters were similar between the 3 treatments. In healthy volunteers, no major watercress effect was observed on ethanol clearance but a weak inhibiting effect on acetaldehyde metabolism is possible. Ethanol absorption is also delayed by single ingestion of watercress immediately preceding ethanol consumption.