From the Editor’s desk...
Authors: Richard Moreau, Ramon Bataller, Thomas Berg, Jessica Zucman-Rossi, Rajiv Jalan
Journal: Journal of Hepatology (2015)

Targeting Toll-like receptor 7 in chronic HBV infection ECT2 is encoded by epithelial cell transforming 2 (ECT2, alias ARHGEF31). It is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on the Rho family members of small GTPases, like RHOA, RHOC, RAC1, and CDC42. Rho GTPases via actin activation coordinate cell migration and affect cancer invasion and metastasis, among other processes. Because ECT2 is a major regulator of Rho GTPases, Chen et al. asked whether this protein plays a role in HCC recurrence after surgical resection. Performing expression microarray confirmed an overexpression of ECT2 transcripts in HCC tissues compared with non-tumoral liver. Moreover they found that ECT2 overexpression is associated with early recurrent HCC disease and poor survival. Elegant in vitro mechanistic studies led to a scenario in which ECT2 via the activation of Rho GTPases stimulates MAP kinases ERK to promote early HCC recurrence. These findings suggest that ECT2 could be a target for novel therapies aimed to prevent HCC recurrence. Sustained activation (i.e., phosphorylation) of c-Jun N-terminal kinase (JNK, a MAP kinase) by saturated fatty acids plays a role in lipotoxicity and the development of NASH. Win et al. investigating in vitro phosphatidic acid (PA)-induced hepatocyte toxicity now show that JNK activation is dependent on upstream stimulation of PRKR-like endoplasmic reticulum (ER) kinase (PERK) indicating the engagement of an unfolded protein response due to PA-induced ER stress. They also found that the interplay of activated JNK with the mitochondrial protein Sh3bp-5 (also known Sab) leads to impaired mitochondrial respiration (i.e., stress of the organelle), ROS production, sustained JNK activation, and apoptosis. These findings suggest that ER stress may mediate hepatocyte lipotoxicity at least in part via inducing Sh3bp-5–elicited mitochondrial stress. Intracellular pattern recognition receptors that assemble into high-molecular weight, caspase-1-activating platforms called ‘inflammasomes’ (e.g., NLRP3) control maturation and secretion of interleukins (IL) such as IL-1β and IL-18, which both are potent pro-inflammatory cytokines. In mouse models of alcohol-induced steatohepatitis the NLRP3 inflammasome is activated in Kupffer cells, resulting in the release of IL-1β. However, little is known about the contribution of IL-1β to liver inflammation. Cui et al. addressed this question using a chronic plus single-binge ethanol consumption model in wild-type and Jα18−/− mice that are deficient in invariant natural killer T (iNKT) cells. They show that Kupffer cell-derived IL-1β, produced after alcohol-induced NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury. Therefore, IL-1β could be a target for anti-inflammatory therapies in patients with alcoholic liver disease. Epiplakin (encoded by Eppk1) is a member of the plakin protein family which maintains the integrity of keratin intermediate filament networks in epithelial cells. Epiplakin-deficient (Eppk1−/−) mice have no obvious spontaneous phenotype but the consequences of Eppk1 deficiency in the context of liver injury is unknown. For this reason, Szabo et al. investigated wild-type and Eppk1−/− mice subjected to common bile duct ligation (CBDL) or fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet. After CBDL and DDC treatment, Eppk1−/− mice exhibited more marked liver injury and their livers contained larger amounts of hepatocellular keratin granules, indicating impaired disease-induced keratin network reorganization. Overall their data are consistent with the view that epiplakin plays a protective role during experimental liver injuries by chaperoning disease-induced keratin reorganization. Liver sinusoidal endothelial cells (LSECs) can contribute to hepatic tolerance through their ability to induce CD4+ Foxp3+ regulatory T cells (Tregs). Carambia et al. asked whether the Treg-inducing potential of LSECs could be used for the treatment of autoimmune disease. To address this question they engineered a polymeric nanoparticle (NP) carrier that selectively delivers autoantigen peptides to LSECs in vivo. Next they investigated whether administration of LSEC-targeting autoantigen peptide-loaded NPs protects mice with experimental autoimmune encephalomyelitis. They found that selective delivery of autoantigen peptides to LSECs by NPs induces antigen-specific Tregs and is associated with improvement of autoimmune disease. These findings emphasize the importance of Treg-induction by LSECs in obtaining immune tolerance. NAFLD is frequently associated with other medical conditions. In this issue, two large studies liked NAFLD with hyperuricemia and celiac disease. Hyperuricemia is a common feature of patients with obesity. Xu et al. carried out a human and experimental study that showed that NAFLD significantly increases the risk of incident hyperuricemia, and that xanthine oxidase is a mediator of the relationship between two conditions. Interestingly, they provide evidence that targeting xanthine oxidase could have beneficial effects on NAFLD. Celiac disease alters intestinal permeability and gluten-free diet often causes weight gain. Reilly et al. performed a population-based cohort study, demonstrating that patients with celiac disease are at increased risk of NAFLD compared to the general population. This epidemiological study suggests that upon diagnosis, patients with celiac disease should be advised to avoid weight gain and subsequent NAFLD development. Besides changes in lifestyle, current efforts have been made to identify new therapeutic targets for patients with NAFLD. There is recent evidence that bile acids contribute to NAFLD and are targets for therapy. In this issue, Mueller et al. demonstrate that by exerting FXR-antagonistic effects, treatment with ursodeoxycholic acid strongly impacts on cholesterol and bile synthesis and induces neutral lipid accumulation in both liver and visceral fat. These interesting results provide evidence that bile acids regulate steatosis and open new pathways for therapeutic interventions. Endogenous cannabinoids are one of the most promising therapeutic targets for NAFLD. In this issue, Silvestri et al. provide evidence that delta9-tetrahydrocannabivarin and cannabidiol, two endogenous cannabinoids, improve insulin sensitivity and reduce experimental liver steatosis. These results confirm that this family of substances has enormous potential to treat patients with metabolic syndrome and NAFLD. The development of targeted therapies for ALD requires the identification of the molecular drivers. It is not well known whether alcohol-metabolizing enzymes contribute to liver damage. High-throughput screening has previously identified N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) as a potent activator of aldehyde dehydrogenase, mitochondrial (also known as ALDH class 2). In this issue of the Journal, Zhong et al. demonstrates that Alda-1, a specific activator of ALDH2, accelerates acetaldehyde clearance and attenuates liver damage after alcohol exposure. This intriguing study suggests that ALDH class 2 is a promising molecular target and Alda-1 has therapeutic potential for treating ALD. Intestinal failure due to the loss of ileum is associated with chronic liver injury, yet the underlying mechanisms are unknown. In this issue, Mutanen et al. investigated role of fibroblast growth factor 19 (FGF-19) and pro-inflammatory cytokines. In pediatric onset intestinal failure, loss of ileum decreases serum FGF-19 concentration paralleling hepatic inflammation and fibrosis along with increased cholesterol synthesis. This study suggests that FGF-19 may contribute to the pathogenesis of liver disease associated to this syndrome. Although interferon-based regimen will ultimately disappear in the management of chronic HCV infection (due to the rapid development of interferon-free DAA regimens), and faldaprevir may ultimately have a limited clinical role as Boehringer Ingelheim stopped their HCV development program, the results of the current phase III faldaprevir triple therapy study by Ferenci et al. marks an important milestone in HCV therapeutics. Relevant questions have been addressed within this study especially regarding the importance of dosage and duration of protease inhibitor applications in general, predictors of treatment outcome including the relevance of baseline resistance associated variants and viral polymorphisms but also the safety of second-wave protease inhibitor regimens. A population-based study from two Eastern French administrative areas with a total population of about one million indicates an increased overall mortality from chronic HBV infection of 70% as compared to the general population. After a median follow-up of over 8 years, significant increased risk of death was due to hepatocellular carcinoma, non-Hodgkin’s lymphoma (NHL) and chronic liver disease. Thus, the study by Montuclard et al. confirms previous findings which have linked chronic HBV to the development of NHL. Unfortunately, the effect of antiviral treatment could not be investigated in the current study. The study by Wolffram et al. represents one of the largest prospective studies which evaluates the prevalence of chronic HBV and HCV infection in the primary care setting (named ‘Check-up 35+’) in Germany in a cohort of 21,000 persons, and is probably the first which critically evaluates the clinical benefit of a hepatitis screening according to risk scenarios defined by national treatment guidelines. Three easy to apply questions could be extracted for daily clinical routine which were significantly associated with the presence of chronic hepatitis virus infection; i.e. for HBV: immigration, infection in household and male gender; and for HCV: intravenous drug use, blood transfusion before 1992, and immigration. In combination with elevated ALT, these questions identified 83% of previously unknown HCV RNA positive patients by screening only 26% of the overall population. In contrast, this study failed to confirm that birth cohort screening (‘baby boomers’) as recommended in the US allows identification of subgroups of individuals in whom the prevalence of viral hepatitis is especially high indicating the need for country-specific screening strategies.