Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH), disorders that increase ...risk of hepatocellular carcinoma (HCC). To determine whether and how ER stress contributes to obesity-driven hepatic tumorigenesis we fed wild-type (WT) and MUP-uPA mice, in which hepatocyte ER stress is induced by plasminogen activator expression, with high-fat diet. Although both strains were equally insulin resistant, the MUP-uPA mice exhibited more liver damage, more immune infiltration, and increased lipogenesis and, as a result, displayed classical NASH signs and developed typical steatohepatitic HCC. Both NASH and HCC development were dependent on TNF produced by inflammatory macrophages that accumulate in the MUP-uPA liver in response to hepatocyte ER stress.
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•A mouse model is created for high-fat-diet (HFD)-induced NASH and HCC•ER stress increases NASH and HCC risk in response to HFD•NASH and HFD-driven HCC depend on TNF and IKKβ signaling•ER stress increases NASH and HCC risk independently of insulin resistance
Nakagawa et al. examine the role of ER stress in obesity-driven hepatic tumorigenesis. They find that ER stress increases the risk of high-fat diet-induced nonalcoholic steatohepatitis and hepatocellular carcinoma and concurrently develop a mouse model of the disease based on these findings.
Compensatory proliferation triggered by hepatocyte loss is required for liver regeneration and maintenance but also promotes development of hepatocellular carcinoma (HCC). Despite extensive ...investigation, the cells responsible for hepatocyte restoration or HCC development remain poorly characterized. We used genetic lineage tracing to identify cells responsible for hepatocyte replenishment following chronic liver injury and queried their roles in three distinct HCC models. We found that a pre-existing population of periportal hepatocytes, located in the portal triads of healthy livers and expressing low amounts of Sox9 and other bile-duct-enriched genes, undergo extensive proliferation and replenish liver mass after chronic hepatocyte-depleting injuries. Despite their high regenerative potential, these so-called hybrid hepatocytes do not give rise to HCC in chronically injured livers and thus represent a unique way to restore tissue function and avoid tumorigenesis. This specialized set of pre-existing differentiated cells may be highly suitable for cell-based therapy of chronic hepatocyte-depleting disorders.
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•Hybrid hepatocytes (HybHP) constitutively reside in portal triads of healthy liver•HybHP can replenish the entire parenchyma after chronic hepatocyte damage•Despite multiple divisions, HybHP do not originate HCC in three independent models•HybHP exhibit unmatched regenerative capacity in a diseased liver
Hybrid hepatocytes (HybHP) are a subpopulation of periportal hepatocytes that are present in the healthy liver and that undergo extensive proliferation and replenish liver mass after chronic hepatocyte-depleting injuries without giving rise to hepatocellular carcinoma. Isolated HybHP display an unmatched capacity to restore liver function after transplantation into a diseased liver, underscoring their therapeutic potential.
Emerging data suggest that a 30% relative decline in liver fat, as assessed by MRI-proton density fat fraction (MRI-PDFF), may be associated with Non-Alcoholic Fatty Liver Disease Activity Score ...improvement, but the association between decline in MRI-PDFF and fibrosis regression is not known. Therefore, we aimed to examine the association between ≥30% relative decline in MRI-PDFF and fibrosis regression in non-alcoholic fatty liver disease (NAFLD).
This prospective study included 100 well-characterised patients with biopsy-proven NAFLD with paired contemporaneous MRI-PDFF assessment at two time points. MRI-PDFF response was defined as ≥30% relative decline in MRI-PDFF. The
was ≥1 stage histological fibrosis regression.
The median (IQR) age was 54 (43-62) years and body mass index was 31.9 (29-36) kg/m
. In multivariable-adjusted logistic regression analysis (adjusted for age, gender, diabetes status, race/ethnicity, interval between biopsies, gamma-glutamyl transferase, liver stiffness by magnetic resonance elastography and change in platelet counts), MRI-PDFF response was an independent predictor of fibrosis regression with an adjusted OR of 6.46 (95% CI 1.1 to 37.0, p=0.04). The proportion of patients with MRI-PDFF response with fibrosis regression, no change in fibrosis and fibrosis progression was 40.0%, 24.6% and 13.0%, respectively, and the proportion of patients with MRI-PDFF response increased with fibrosis regression (p=0.03).
≥30% reduction in MRI-PDFF in early phase trials can provide a useful estimate of odds of ≥1 stage improvement in fibrosis. These data may be helpful in sample size estimation in non-alcoholic steatohepatitis trials.
How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular ...relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors.
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•CD44 promotes HCC initiation by protecting DNA-damaged hepatocytes•MDM2 nuclear translocation is facilitated by CD44-coupled EGFR-AKT signaling axis•CD44 terminates DNA damage-induced p53 response, cell-cycle exit, and apoptosis•STAT3 regulates Cd44 expression in hepatocytes
Dhar et al. show that CD44 expression induced in carcinogen-exposed hepatocytes potentiates AKT signaling to activate Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to respond to proliferative signals, leading their daughter cells to become HCC progenitors.
p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate ...in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death.
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•p62 in preneoplastic lesions is important for HCC development regardless of etiology•Ectopic p62 expression is sufficient for HCC induction in autophagy-competent liver•p62 exerts its oncogenic activity via NRF2 and mTORC1 but not via ubiquitin binding•p62 promotes survival and expansion of ROS-containing HCC-initiating cells
Umemura et al. employ several mouse models of HCC to demonstrate that p62 facilitates activation of NRF2 and mTORC1 and is essential for HCC initiation. High levels of p62 accumulation in non-tumor liver tissue in early-stage HCC patients undergoing curative ablation correlates with reduced overall survival.
Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and ...profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2-4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.
Background & Aims Magnetic resonance imaging (MRI) techniques and ultrasound-based transient elastography (TE) can be used in noninvasive diagnosis of fibrosis and steatosis in patients with ...nonalcoholic fatty liver disease (NAFLD). We performed a prospective study to compare the performance of magnetic resonance elastography (MRE) vs TE for diagnosis of fibrosis, and MRI-based proton density fat fraction (MRI-PDFF) analysis vs TE-based controlled attenuation parameter (CAP) for diagnosis of steatosis in patients undergoing biopsy to assess NAFLD. Methods We performed a cross-sectional study of 104 consecutive adults (56.7% female) who underwent MRE, TE, and liver biopsy analysis (using the histologic scoring system for NAFLD from the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System) from October 2011 through May 2016 at a tertiary medical center. All patients received a standard clinical evaluation, including collection of history, anthropometric examination, and biochemical tests. The primary outcomes were fibrosis and steatosis. Secondary outcomes included dichotomized stages of fibrosis and nonalcoholic steatohepatitis vs no nonalcoholic steatohepatitis. Receiver operating characteristic curve analyses were used to compare performances of MRE vs TE in diagnosis of fibrosis (stages 1–4 vs 0) and MRI-PDFF vs CAP for diagnosis of steatosis (grades 1–3 vs 0) with respect to findings from biopsy analysis. Results MRE detected any fibrosis (stage 1 or more) with an area under the receiver operating characteristic curve (AUROC) of 0.82 (95% confidence interval CI, 0.74–0.91), which was significantly higher than that of TE (AUROC, 0.67; 95% CI, 0.56−0.78). MRI-PDFF detected any steatosis with an AUROC of 0.99 (95% CI, 0.98−1.00), which was significantly higher than that of CAP (AUROC, 0.85; 95% CI, 0.75−0.96). MRE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.89 (95% CI, 0.83−0.96), 0.87 (95% CI, 0.78−0.96), and 0.87 (95% CI, 0.71−1.00); TE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.86 (95% CI, 0.77−0.95), 0.80 (95% CI, 0.67–0.93), and 0.69 (95% CI, 0.45–0.94). MRI-PDFF identified steatosis of grades 2 or 3 with AUROC values of 0.90 (95% CI, 0.82−0.97) and 0.92 (95% CI, 0.84−0.99); CAP identified steatosis of grades 2 or 3 with AUROC values of 0.70 (95% CI, 0.58−0.82) and 0.73 (95% CI, 0.58−0.89). Conclusions In a prospective, cross-sectional study of more than 100 patients, we found MRE to be more accurate than TE in identification of liver fibrosis (stage 1 or more), using biopsy analysis as the standard. MRI-PDFF is more accurate than CAP in detecting all grades of steatosis in patients with NAFLD.
Ezetimibe inhibits intestinal cholesterol absorption and lowers low‐density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in ...nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging‐derived proton density‐fat fraction (MRI‐PDFF) and liver histology in patients with biopsy‐proven NASH. In this randomized, double‐blind, placebo‐controlled trial, 50 patients with biopsy‐proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI‐PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two‐dimensional and three‐dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI‐PDFF (mean difference between the ezetimibe and placebo arms ‐1.3%, P = 0.4). Compared to baseline, however, end‐of‐treatment MRI‐PDFF was significantly lower in the ezetimibe arm (15%‐11.6%, P < 0.016) but not in the placebo arm (18.5%‐16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two‐dimensional and three‐dimensional magnetic resonance elastography‐derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI‐PDFF (‐4.35 ± 4.9% versus ‐0.30 ± 4.1%, P < 0.019). Conclusions: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI‐PDFF‐derived fat maps and magnetic resonance elastography‐derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH. (Hepatology 2015;61:1239–1250)
Background and Aims
Patients with NAFLD with significant hepatic fibrosis (Stage ≥ 2) are at increased risk of liver‐related morbidity and are candidates for pharmacologic therapies. In this study, ...we compared the diagnostic accuracy of MEFIB (the combination of magnetic resonance elastography MRE and Fibrosis‐4 FIB‐4) and FAST (FibroScan–aspartate aminotransferase; combined liver stiffness measurement by vibration‐controlled transient elastography, controlled attenuation parameter, and aspartate aminotransferase) for detecting significant fibrosis.
Approach and Results
This prospective cohort study included 234 consecutive patients with NAFLD who underwent liver biopsy, MRE, and FibroScan at the University of California San Diego (UCSD cohort) and an independent cohort (N = 314) from Yokohama City University, Japan. The primary outcome was diagnostic accuracy for significant fibrosis (Stage ≥ 2). The proportions of significant fibrosis in the UCSD and Yokohama cohorts were 29.5% and 66.2%, respectively. Area under the receiver operating characteristic curve (95% CI) of MEFIB (0.860 0.81–0.91) was significantly higher than that of FAST (0.757 0.69–0.82) in the UCSD cohort (p = 0.005), with consistent results in the Yokohama cohort (AUROC, 0.899 MEFIB versus 0.724 FAST; p < 0.001). When used as the rule‐in criteria (MEFIB, MRE ≥ 3.3 kPa and FIB‐4 ≥ 1.6; FAST ≥ 0.67), the positive predictive value for significant fibrosis was 91.2%–96.0% for MEFIB and 74.2%–89.2% for FAST. When used as the rule‐out criteria (MEFIB, MRE < 3.3 kPa and FIB‐4 < 1.6; FAST ≤ 0.35), the negative predictive value for significant fibrosis was 85.6%–92.8% for MEFIB and 57.8%–88.3% for FAST.
Conclusions
MEFIB has higher diagnostic accuracy than FAST for significant fibrosis in NAFLD, and our results support the utility of a two‐step strategy for detecting significant fibrosis in NAFLD.
Obesity can result in insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH) and increases liver cancer risk. Obesity-induced insulin resistance depends, in part, on chronic ...activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer. Correspondingly, mTORC1 inhibitors have been considered as potential NASH and HCC treatments. Using a mouse model in which high-fat diet enhances HCC induction by the hepatic carcinogen DEN, we examined whether mTORC1 inhibition attenuates liver inflammation and tumorigenesis. Notably, rapamycin treatment or hepatocyte-specific ablation of the specific mTORC1 subunit Raptor resulted in elevated interleukin-6 (IL-6) production, activation of signal transducer and activator of transcription 3 (STAT3), and enhanced HCC development, despite a transient reduction in hepatosteatosis. These results suggest that long-term rapamycin treatment, which also increases IL-6 production in humans, is unsuitable for prevention or treatment of obesity-promoted liver cancer.
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•mTORC1 inhibition results in STAT3 activation•Raptor ablation results in liver damage, inflammation, and oxidative stress•Raptor ablation potentiates hepatocarcinogenesis in lean and obese mice•Prolonged mTORC1 inhibition results in adverse effects on liver physiology
Umemura et al. show that although rapamycin treatment reduced hepatosteatosis, it increased IL-6 production and activated the protumorigenic factor STAT3, and that liver-specific raptor-deficient mice had enhanced hepatocellular carcinoma (HCC), suggesting that long-term mTORC1 inhibition may not be a valid therapeutic option in NASH or steatotic HCC.
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