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

Exercise: Treatment for NAFLD Platelet-derived growth factor receptor beta (PDGFR-β) belongs to the large family of receptor tyrosine kinases (RTKs) that are expressed at the cell-surface. Rapid induction of PDGFR-β is a hallmark of hepatic stellate cell activation; however, little is known on its cellular impact in vivo. To address this question Kocabayoglu et al. used in vitro approaches, in vivo mice models of liver injury and HCC, and a cohort of patients with hepatitis C virus-related cirrhosis (with or without HCC). They found that PDGFR-β is a key mediator of liver injury and fibrogenesis in vivo and contributes to the poor prognosis of human cirrhosis, but not by increasing HCC development. Together these findings deserve two comments: first, PDGFR-β is an attractive anti-fibrotic target; and second, unlike other RTK pathways such as epidermal growth factor receptor, PDGFR-β may not be a suitable direct target to inhibit the development of HCC. Toll-like receptor (TLR) 9, expressed in endosomes of innate immune cells, recognize bacterial and viral DNA containing the unmethylated cytosine–phosphate–guanine (CpG) dideoxynucleotide motif. TLR9 recognition of CpG-containing DNA (CpG-DNA) triggers MyD88-mediated inflammation. There is evidence that TLR9 can also be activated by ‘non-microbial’ CpG-DNA. Dying non-tumoral cells release danger-associated molecular patterns (DAMPs) of different subcellular origin, e.g., the nuclear, non-histone protein, high mobility group box-1 (HMGB1) or mitochondrial DNA (mtDNA), among others. In the context of auto-immune diseases HMGB1 is an essential component of DNA-containing immune complexes that stimulate cytokine production through a TLR9 pathway. Interestingly, mtDNA has similarities to bacterial DNA, which contains unmethylated CpG motifs. After severe trauma, released mtDNA can activate innate immune cells via TLR9 engagement. Liu et al. reasoned that cell death resulting from hypoxia at the center of the HCC tumor may release HMGB1 and mtDNA and this would contribute to inflammation and tumor promotion. They address their hypothesis using in vivo and in vitro approaches and provide convincing results (this issue of the Journal) showing that interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce HCC growth. It has long been known that cyclin-dependent-like kinase 5 (CDK5) is essential for neuronal cell cycle arrest and differentiation. Moreover, it has recently been suggested that CDK5 is involved in cancer progression. Using different approaches including expression microarray in human HCC tissue Ehrlich et al. investigated CDK5 as a potential target for treating patients with HCC. They found that CDK5 inhibition combined to DNA damaging agents is a novel therapeutic approach for HCC. Several staging systems are used to predict survival in patients with HCC. However, the ability of most of these staging systems in predicting survival in patients with unresectable HCC after transarterial chemoembolization (TACE) is limited. Xu et al. addressed this question by constructing a nomogram based on data obtained from a retrospective study on 2938 patients who received TACE as an initial therapy from 2000 to 2008. Portal vein invasion, tumor number, tumor capsule, α-fetoprotein, aspartate aminotransferase, and indocyanine green retention at 15 min were the basis of the nomogram. The nomogram gave better discrimination than the seven other well-established staging systems. Therefore, the proposed nomogram provides accurate prognostic prediction in patients with unresectable HCC after treatment with TACE. In the context of HCC, the benefit of TACE prior to liver resection or transplantation is unclear. Allard et al. hypothesized that the amount of TACE-induced tumor necrosis assessed by two expert pathologists on surgical specimens could provide prognostic information. They investigated 373 cirrhotic patients with HCC treated first by TACE and then by liver resection (n = 184) or transplantation (n = 184). The response assessed by pathologists (RAP) was the mean percentage of non-viable tumor area within each tumor. Complete RAP was defined as the absence of any viable tumor area in all the present nodules. They found that a complete or nearly complete RAP is associated with higher long-term survival after liver resection or transplantation, independent of other pathological factors. These findings support, prior to surgery for HCC, the use of therapies that induce significant decreases in the active tumor load. The incidence of metabolic syndrome (MS)-associated with HCC (MS-HCC) is increasing. Little is known on the outcomes after liver resection in patients with MS-HCC. This is why Vigano et al. investigated retrospectively 1563 consecutive patients who underwent liver resection for HCC in six high-volume liver units in 12 years. Patients with MS-HCC were matched with HCV-related HCC patients who did not have MS. They found that liver resection was safe in patients with HCC and MS as well as in patients with HCV-related HCC and no MS. Cirrhosis, but not steatohepatitis, was the main predictor of poor short-term outcomes. MS-HCC was associated with excellent long-term outcomes, better than outcomes in patients with HCV-related HCC and no MS. Three studies in this issue propose novel targets for therapy for NAFLD. Francque et al. provide consistent human data implicating peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of NASH. They found that hepatic PPARα gene expression negatively correlated with NASH severity, visceral adiposity and insulin resistance, suggesting that it could be a therapeutic target in NASH. Wang et al. now investigate the role of hepatic estrogen receptor α (ERα) in triglyceride homeostasis and fatty liver development. Female mice receiving ovariectomy or genetic ablation of the ERα receptor genetic ablation induced hepatic triglyceride accumulation, while overexpression of ERα ameliorated hepatosteatosis in obese mice. These findings reveal a novel role of estrogen in improving hepatosteatosis. The molecular mechanisms of ALD are partially known. In this issue, Huang et al. demonstrate a critical role for the Wnt/β-catenin signaling pathway, which restored attenuation of ALD in rats. The authors also demonstrated that this effect was associated with a blockade of Foxo3A-induced apoptosis. Drugs targeting this pathway could be beneficial for patients with ALD. Patients with Wilson’s disease often have hepatic steatosis, yet the underlying mechanisms are largely unknown. In this issue, Stättermayer et al. provide evidence that steatosis is common in these patients and the PNPLA3 G allele contributes to its pathogenesis. They also propose a potential role for hepatic copper content and ATP7B (for ATPase, Cu++ transporting, beta polypeptide) mutations in steatosis development, yet the precise mechanisms deserve future investigations. This study suggests that, regardless of the etiology, PNPLA3 is an important genetic determinant of hepatic steatosis. The all oral combination of the protease inhibitor asunaprevir plus the NS5A inhibitor daclatasvir has demonstrated high efficacy in HCV subtype 1b but not 1a infection. A large open-label, phase 3 study (HALLMARK-QUAD) in a difficult to treat population of mainly null responder patients with HCV type 1 and 4 infection was prospectively evaluated by Jensen et al. to determine if adding peginterferon plus ribavirin in order to get a full quadruple regimen applied for 24 weeks is able to overcome these limitations. SVR rates of 100% in HCV type 4, 99% in HCV subtype 1b, and 87% in subtype 1a highlight to the overall effectiveness of the regimen. Interestingly, however, adding peginterferon and ribavirin did not completely abrogate HCV subtype 1a effects especially for those harbouring protease- and or NS5A-inhibitor associated baseline resistant variants. Attention to DDI is highly relevant for the judicious use of HCV direct-acting antiviral (DAA) regimen as all DAA have the potential to interact with drug metabolizing enzymes and/or drug transporters. The study by Menon et al. represents the first comprehensive evaluation of DDIs for the 3D regimen of ombitasvir, paritaprevir/ritonavir and dasabuvir and medications likely to be co-prescribed in HCV-infected patients also including opioid substitution substances. Although the majority of the commonly used medications can be co-administered with the regimen without dose adjustment, gemfibrozil, carbamazepine and ethinyl estradiol-containing contraceptives are contraindicated. Findings are of significant importance for the appropriate clinical management, which sometimes requires dose adjustments or discontinuation of contraindicated medications. Human cytomegalovirus 1 (HCMV) infection can promote hepatic inflammation and facilitate chronic organ rejection in liver transplant recipients. By an extensive set of experiments, Bruns et al. now elegantly describes that HCMV infection of human sinusoidal endothelial cells plays a crucial role in modulating the recruitment and differentiation of T cell subsets thereby providing important novel insights into the mechanism of how HCMV infection is able to enhance hepatic immune activation. Although a strong CD8+ T cell response is associated with spontaneous HBsAg clearance after acute hepatitis B virus (HBV) infection its role in maintaining immune control in the long-term is rather unclear. Reactivation of HBV infection in immune controlled patients has been linked, however, to monoclonal antibody-induced B cell depletion (i.e., rituximab). In line with these clinical observations, Kefalakes et al. now demonstrate that HBeAg-specific CD8+ T cells continuously decline after HBsAg clearance suggesting that humoral and not CD8+ T cell immune responses mainly contribute to the prevention of HBV reactivation decades after HBsAg clearance. The mechanism of cell death is unknown in patients with acute on chronic liver failure (ACLF). In patients with alcoholic cirrhosis, who develop ACLF, the predominant mechanism of liver injury is apoptosis and bilirubinostasis is the main histological finding. Li et al. describe important data from patients with ACLF due to hepatitis B from China, where histological characteristics of the livers were studied in organs obtained at transplantation. Their data suggest that the predominant mode of cell death in ACLF is sub-massive hepatic necrosis, which they suggest to be a diagnostic hallmark. Infection and inflammation are the consequence of altered host response to injury in cirrhosis. Shi et al. provide novel data that, hepatitis A virus cellular receptor 2 (HAVcr-2, also known as T cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM-3)) is down regulated in the circulating monocytes in decompensated cirrhosis due to Hepatitis B virus infection. This finding may be important in explaining the basis of increased sensitivity to endotoxin in this situation and may well be a future target of therapy. The risk of post-transplantation complications and graft failure is higher in patients transplanted with DCD organs. Liu et al. describe a novel approach to try and reduce injury to the donor organ. They use liver transplantation techniques in the mouse to show that inhibition of or the absence of iNOS, JNK inhibition and JNK 2 deficiency are targets of therapy. The downstream mechanism of this protective effect is via inhibiting mitochondrial depolarization. Kim et al. describe a potential novel approach to the prevention and treatment of APAP-induced acute liver failure (ALF) in ALF mice using, a safe and widely used drug, metformin. The mechanism of this protective effect of metformin is through growth arrest and DNA damage-inducible 45 beta (Gadd45β)-dependent regulation of the JNK pathway.