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.
There is a long history of surgical treatment for Parkinson’s disease (PD). Currently, deep brain stimulation (DBS) has been performed as promising treatment option for medically refractory PD. DBS ...is an adjustable and reversible treatment using implanted medical devices to deliver electrical stimulation to precisely targeted areas of the brain. DBS modulates neurological function of the target region. The most common target for PD is the subthalamic nucleus (STN). DBS is particularly indicated for patients suffering from motor complications of dopaminergic medication such as fluctuations and dyskinesia. Although there is currently no curative treatment for PD, a combination of medical treatment and DBS provide long-term relief of motor symptoms. In this review, I introduce history, mechanism, indication, clinical outcome, complication, long term outcome, timing of surgery, surgical procedure, and current new technology concerning DBS for PD.
Aim
We aimed to develop a novel noninvasive test using an artificial intelligence (AI)/neural network (NN) system (named nonalcoholic steatohepatitis NASH‐Scope) to screen nonalcoholic fatty liver ...disease (NAFLD) and NASH.
Methods
We enrolled 324 and 74 patients histologically diagnosed with NAFLD for training and validation studies, respectively. Two independent pathologists histologically diagnosed patients with NAFLD for validation study. Additionally, 48 subjects who underwent a medical health checkup and did not show fatty liver ultrasonographically and had normal serum aminotransferase levels were categorized as the non‐NAFLD group. NASH‐Scope was based on 11 clinical values: age, sex, height, weight, waist circumference, aspartate aminotransferase, alanine aminotransferase, γ‐glutamyl transferase, cholesterol, triglyceride, and platelet count.
Results
The sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operator characteristic curve of NASH‐Scope for distinguishing NAFLD from non‐NAFLD in the training study and validation study were 99.7% versus 97.2%, 97.8% versus 97.8%, 99.7% versus 98.6%, 97.8% versus 95.7%, and 0.999 versus 0.950, respectively. Those for distinguishing NASH with fibrosis from NAFLD without fibrosis were 99.5% versus 90.7%, 84.3% versus 93.3%, 94.2% versus 98.0%, 98.6% versus 73.7%, and 0.960 versus 0.950. These results were excellent, even when the output data were divided into two categories without any gray zone.
Conclusions
The AI/NN system, termed as NASH‐Scope, is practical and can accurately differentially diagnose between NAFLD and non‐NAFLD and between NAFLD without fibrosis and NASH with fibrosis. Thus, NASH‐Scope is useful for screening nonalcoholic fatty liver and NASH.
Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho ...(KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs' disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis.
Background
The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma ...(HCC) treated with molecular-targeted agents (MTAs).
Methods
Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared.
Results
The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (
p
= 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (
p
= 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months;
p
= 0.039, and 18.1 months vs 11.3 months;
p
= 0.019). At the end of first-line MTA therapy, the albumin–bilirubin (ALBI) score in the SVR group ( – 2.25) was significantly lower than that in the non-SVR group ( – 2.10) (
p
= 0.008).
Conclusions
The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients.
Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.
Since many hepatomegaly-inducing toxicants and ...stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2Act-hep mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7Δhep) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology.
Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly.
NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors.
Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
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•Liver p62 accumulation and constitutive NRF2 activation lead to liver lipid buildup, glycogen synthesis and hepatomegaly.•NRF2 activation mediates transcriptional induction of PDGF and EGF receptor ligands that activate AKT.•AKT and tyrosine kinase inhibitors block NRF2-mediated AKT activation and hepatomegaly.•NRF2-AKT signaling is elevated in HSOS- and AIH-related human hepatomegaly.
Aim
To develop a novel noninvasive test using an artificial intelligence (AI)/neural network (NN) system (named Fibro‐Scope) to determine the fibrosis stage in nonalcoholic steatohepatitis (NASH).
...Methods
Three hundred twenty‐four and 110 patients with histologically diagnosed nonalcoholic fatty liver disease (NAFLD) were enrolled for training and validation studies, respectively. Two independent pathologists histologically diagnosed patients with NAFLD for the validation study. Fibro‐Scope was undertaken using 12 items: age, sex, height, weight, waist circumference, aspartate aminotransferase, alanine aminotransferase, γ‐glutamyl transferase, cholesterol, triglyceride, platelet count, and type 4 collagen 7s.
Results
Differentiation of F0 versus F1–4 using the Fibro‐Scope revealed 99.5% sensitivity, 90.9% specificity, 97.4% positive predictive value, and 98.0% negative predictive value in a training study with gray zone analysis, which was also effective in the analysis without gray zone. Discrimination was also excellent when comparing F0–1 versus F2–4 and F0–2 versus F3–4. In a validation study with gray zone analysis, differentiation of F0 from F1–4 using Fibro‐Scope was also excellent. The discrimination of F0–1 from F2–4 using Fibro‐Scope with gray zone analysis showed over 80% sensitivity and specificity in the histological diagnosis of both pathologists, but was lower without the gray zone analysis. The discrimination of F0–2 from F3–4 was effective in the analysis with gray zone; however, their sensitivity and specificity were slightly inferior in the analysis without gray zone.
Conclusions
Artificial intelligence/neural network algorithms termed Fibro‐Scope are easy to use and can accurately differentially diagnose minimal, moderate, and advanced fibrosis. Fibro‐Scope will promote rapid NASH diagnosis and facilitate diagnosing the fibrosis stage in NASH.
During the past 20 to 30 years, the frequency of patients presenting with nonalcoholic fatty liver diseases (NAFLD) has increased gradually in Japan in proportion to the increase in the population ...with life‐style related diseases. We describe here the current status of the clinical and basic aspects of research into NAFLD in Japan.
The increase in the incidence of life‐style‐related diseases has resulted in an increase in NAFLD throughout the past 20 to 30 years. The rate of obesity in the population is not high compared to western countries but the incidence of NAFLD is similar to those countries. In 2008 we started a nationwide study of NAFLD which has been supported by the Ministry of Labor and Welfare Japan. In this project, we planned to investigate the epidemiology, genetic backgrounds and biochemical markers, and liver injury in patients with diabetes mellitus (DM) and hepatocellular carcinoma in NASH, and treatment of NASH. Approximately 20 to 25% of DM patients showed NAFLD in which the prevalence of NASH might be more than 30 to 40%. Fortunately, we have been able to obtain very interesting results from our group studies, including single necleotide polymorphisms (SNPs) which will be published in the near future.
Enhanced de novo lipogenesis mediated by sterol regulatory element-binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed ...the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.
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