Inter-individual variations in circadian misalignment-induced NAFLD pathophysiology in mice.

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of intrinsic behavioral rhythms were found to significantly correlate with CJL-induced gene signatures. Together, our results suggest circadian rhythm robustness of the animals contributes to inter-individual variations in pathogenesis of circadian misalignment-induced diseases and raise the possibility that these physiological indicators may be available for predictive hallmarks of circadian rhythm disorders.

Free-water diffusion magnetic resonance imaging under selegiline treatment in Parkinson's disease.

INTRODUCTION: Monoamine oxidase type B inhibitors, including selegiline, are established as anti-Parkinsonian Drugs. Inhibition of monoamine oxidase type B enzymes might suppress the inflammation because of inhibition to generate reactive oxygen species. However, its effect on brain microstructure remains unclear. The aim of this study is to elucidate white matter and substantia nigra (SN) microstructural differences between Patients with Parkinson's disease with and without selegiline treatment by two independently recruited cohorts. METHODS: Diffusion tensor imaging and free water imaging indices of WM and SN were compared among 22/15 Patients with Parkinson's disease with selegiline (PDselegiline(+)), 33/23 Patients with Parkinson's disease without selegiline (PDselegiline(-)), and 25/20 controls, in the first/second cohorts. Two cohorts were analyzed with different MRI protocols. RESULTS: Diffusion tensor imaging and free-water indices of major white matter tracts were significantly differed between the PDselegiline(-) and controls in both cohorts, although not between the PDselegiline(+) and controls except for restricted areas. Compared with the PDselegiline(+), free-water was significantly higher in the PDselegiline(-) in the inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and superior and posterior corona radiata (first cohort) and the forceps major and splenium of the corpus callosum (second cohort). There were no significant differences in free-water of anterior or posterior substantia nigra between PDselegiline(+) and PDselegiline(-). CONCLUSIONS: Selegiline treatment might reduce the white matter microstructural abnormalities detected by free-water imaging in Parkinson's disease.

Three-dimensional gait analysis of the effect of directional steering on gait in patients with Parkinson's disease.

INTRODUCTION: Deep Brain Stimulation (DBS) is an option to treat advanced Parkinson's Disease (PD), but can cause gait disturbance due to stimulation side efffects. This study aims to evaluate the objective effect of directional current steering by DBS on gait performance in PD, utilizing a three-dimensional gait analysis system. METHODS: Eleven patients diagnosed with PD and were implanted with directional lead were recruited. The direction of the pyramidal tract (identified by the directional mode screening) was set as 0°. Patients performed the six-meter-walk test and the time up-and-go (TUG) test while an analysis system recorded gait parameters utilizing a three-dimensional motion capture camera. The gait parameters were measured for the baseline, the directional steering at eight angles (0°, 45°, 90°, 135°, 180°, 225°, 270°, and 315°), and the conventional ring mode with 1, 2, and 3 mA. Pulse width and frequency were fixed. Placebo stimulation (0 mA) was used for a control. RESULTS: Eleven patients completed the study. No significant difference were observed between gait parameters during the directional, baseline, placebo, or ring modes during the six-meter-walk test (p > 0.05). During the TUG test, stride length was significantly different between 0° and other directions (p < 0.001), but no significant differences were observed for the other gait parameters. Stride width was non-significantly narrower in the direction of 0°. CONCLUSION: Controlling stimulation using directional steering may improve gait in patients with PD, while avoiding pyramidal side effects.

Deep brain stimulation in posterior subthalamic area for Holmes tremor: Case reports with review of the literature.

Background: Holmes tremor (HT) is a refractory tremor associated with cortico-basal ganglia loops and cerebellothalamic tract abnormalities. Various drug treatments have been attempted; however, no treatment method has yet been established. Historically, thalamic deep brain stimulation (DBS) has been performed in medically refractory cases. Recently, the posterior subthalamic area (PSA) has been used for HT. Here, we report cases of HT and review the effectiveness and safety of PSA-DBS for HT. Cases: We conducted a retrospective chart review of two patients with HT who underwent PSA-DBS. Improvement in tremors was observed 1 year after surgery without apparent complications. Literature review: We identified 12 patients who underwent PSA-DBS for HT, including our cases. In six patients, PSA was targeted alone; for the rest, the ventralis intermediate nucleus (Vim) of the thalamus and PSA were simultaneously targeted. The Fahn-Tolosa-Marin Tremor Rating Scale improvement rates were 56.8% (range, 33.9-82.1%; n = 6) and 77.8% (range, 42.6-100%; n = 5) for the PSA-DBS and PSA+Vim-DBS, respectively. Conclusion: Reasonable improvements in HT were observed after PSA-DBS. PSA might be an appropriate target for improving the symptoms of HT. Long-term observations, accumulation of cases, and randomized studies are required in future.

Role of the subthalamic nucleus in perceiving and estimating the passage of time.

Sense of time (temporal sense) is believed to be processed by various brain regions in a complex manner, among which the basal ganglia, including the striatum and subthalamic nucleus (STN), play central roles. However, the precise mechanism for processing sense of time has not been clarified. To examine the role of the STN in temporal processing of the sense of time by directly manipulating STN function by switching a deep brain stimulation (DBS) device On/Off in 28 patients with Parkinson's disease undergoing STN-DBS therapy. The test session was performed approximately 20 min after switching the DBS device from On to Off or from Off to On. Temporal sense processing was assessed in three different tasks (time reproduction, time production, and bisection). In the three temporal cognitive tasks, switching STN-DBS to Off caused shorter durations to be produced compared with the switching to the On condition in the time production task. In contrast, no effect of STN-DBS was observed in the time bisection or time reproduction tasks. These findings suggest that the STN is involved in the representation process of time duration and that the role of the STN in the sense of time may be limited to the exteriorization of memories formed by experience.

Comparison of portal vein hemodynamics with ultrasound-based elastography for the prediction of liver fibrosis in patients with chronic liver disease.

Chronic liver disease includes nonalcoholic fatty liver disease, progresses from steatosis and hepatitis to fibrosis and cirrhosis, with hemodynamic changes in portal blood flow. This study aimed to compare portal vein hemodynamics with liver stiffness (LS) and steatosis and included 28 subjects with chronic liver disease, in whom LS and steatosis were evaluated in the same image employing two elastography techniques: transient elastography (TE) with controlled attenuation parameter (CAP) using a FibroScan and two-dimensional shear-wave elastography (2D-SWE) with attenuation imaging (ATI). Additionally, peak maximum velocity (Vmax) of the right portal vein and spleen stiffness with 2D-SWE were evaluated. A strong positive correlation was present between LS values obtained with TE and 2D-SWE and between the attenuation coefficients of steatosis obtained with CAP and ATI. Additionally, a negative correlation was present between LS values and the Vmax of the right portal vein (r = 0.415, p = 0.031). The optimal Vmax cutoff value for discriminating liver fibrosis with an LS value of > 5 kPa was < 17 cm/s; the ability of Vmax to predict fibrosis was comparable to that of the FIB4-index. Low Vmax of the right portal vein was useful for identifying liver fibrosis in patients with chronic liver disease.

Reactive Oxygen Species and NRF2 Signaling, Friends or Foes in Cancer?

The imbalance between reactive oxygen species (ROS) production and clearance causes oxidative stress and ROS, which play a central role in regulating cell and tissue physiology and pathology. Contingent upon concentration, ROS influence cancer development in contradictory ways, either stimulating cancer survival and growth or causing cell death. Cells developed evolutionarily conserved programs to sense and adapt redox the fluctuations to regulate ROS as either signaling molecules or toxic insults. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2)-KEAP1 system is the master regulator of cellular redox and metabolic homeostasis. NRF2 has Janus-like roles in carcinogenesis and cancer development. Short-term NRF2 activation suppresses tissue injury, inflammation, and cancer initiation. However, cancer cells often exhibit constitutive NRF2 activation due to genetic mutations or oncogenic signaling, conferring advantages for cancer cells' survival and growth. Emerging evidence suggests that NRF2 hyperactivation, as an adaptive cancer phenotype under stressful tumor environments, regulates all hallmarks of cancer. In this review, we summarized the source of ROS, regulation of ROS signaling, and cellular sensors for ROS and oxygen (O2), we reviewed recent progress on the regulation of ROS generation and NRF2 signaling with a focus on the new functions of NRF2 in cancer development that reach beyond what we originally envisioned, including regulation of cancer metabolism, autophagy, macropinocytosis, unfolded protein response, proteostasis, and circadian rhythm, which, together with anti-oxidant and drug detoxification enzymes, contributes to cancer development, metastasis, and anticancer therapy resistance.

Fibro-Scope V1.0.1: an artificial intelligence/neural network system for staging of nonalcoholic steatohepatitis.

BACKGROUND: Fibro-Scope is an artificial intelligence/neural network system to determine the fibrosis stage in nonalcoholic steatohepatitis (NASH) using 12 parameters of the patient: age, sex, height, weight, waist circumference (WC), platelet count, and the levels of aspartate and alanine aminotransferase, gamma-glutamyltransferase, cholesterol, triglycerides, and type IV collagen 7S. However, measurement of WC is unstable and often missing from patient databases. Herein, we created Fibro-Scope V1.0.1 that has the same detection power as its predecessor, without the need to consider WC. METHODS: To build a new AI diagnostic system available for the global needs, data from 764 patients with NASH and bridging fibrosis (STELLAR-3) or compensated cirrhosis (STELLAR-4) that participated in two phase III trials were added to the Japanese data. Finally, the data of a total of 898 patients in the training and of 300 patients in the validation studies were analyzed, respectively. RESULTS: The discrimination of F0-2 from F3,4 through Fibro-Scope V1.0.1 was characterized by a 99.8% sensitivity, a 99.6% specificity, a 99.8% positive predictive value, and a 99.6% negative predictive value in a training study with gray zone analysis; similar effectiveness was also revealed in the analysis without a gray zone. In the validation studies with and without gray zone analysis, high sensitivity and specificity were also identified. Fibro-Scope V1.0.1 exerted a diagnostic accuracy for F3,4 advanced fibrosis that was comparable to that of the original Fibro-Scope and delivered high (> 92%) sensitivity and specificity. CONCLUSION: Fibro-Scope V1.0.1 can accurately diagnose F3,4 fibrosis without the need of WC.

Serum levels of immunoglobulin M-free inhibitors of macrophage/CD5L as a predictive and early diagnostic marker for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

BACKGROUND: The apoptosis inhibitor of macrophage (AIM) is usually associated with the immunoglobulin M (IgM) pentamer in the blood and is dissociated from IgM in various diseases, including hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH). We aimed to elucidate whether IgM-free AIM (fAIM) is useful for detecting latent HCC in NASH. METHODS: This research consisted of two cohort studies. The levels of serum fAIM, alpha-fetoprotein (AFP), and des-gamma carboxy prothrombin (DCP) of 18 NASH patients who developed HCC were measured during the follow-up period before HCC diagnosis (median, 4.7 years). In total, 199 patients with nonalcoholic fatty liver disease (NAFLD) were included in the HCC survey. The serum fAIM levels were analyzed using enzyme-linked immunosorbent assays. RESULTS: In the cohort of 18 patients with HCC, 12 had high fAIM at the time of the initial blood sample, three had normal fAIM levels throughout the follow-up period, and three had fAIM elevated from normal to positive. The positive ratio of fAIM prior to HCC diagnosis remained significantly higher than that of AFP and DCP, and the fAIM ratio gradually increased. In a survey of 199 non-HCC NAFLD patients, a Cox regression analysis using independent variables, such as AFP, fAIM, age, albumin, bilirubin, and fibrosis stage, revealed that fAIM and AFP were significantly associated with the incidence of HCC. CONCLUSIONS: During the development of NASH-HCC, AIM activation in blood appears to start even before HCC is diagnostically detectable. Thus, the serum IgM-free AIM levels could be a new, sensitive biomarker for latent NASH-HCC.

Short-Term Motor Outcomes in Parkinson's Disease after Subthalamic Nucleus Deep Brain Stimulation Combined with Post-Operative Rehabilitation: A Pre-Post Comparison Study.

Background: The effects of subthalamic nuclear deep brain stimulation therapy (STN-DBS) and combined postoperative rehabilitation for patients with Parkinson's disease with postural instability have yet to be well reported. This study investigated the effects of short-term postoperative rehabilitation with STN-DBS on physical function in patients with Parkinson's disease. Methods: Patients diagnosed with Parkinson's disease who were admitted to our hospital for STN-DBS surgery were included in this study. Data were prospectively collected and retrospectively analyzed. Postoperative rehabilitation consisted of muscle-strengthening exercises, stretching, and balance exercises for 40-60 minutes per day for approximately 14 days. The Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go test (TUG) seconds and steps, Trunk Impairment Scale (TIS), seconds for 10 times toe-tapping, lower limb extension torque using StrengthErgo240, and center of pressure sway in the quiet standing posture were evaluated preoperatively, postoperatively, and at discharge. Mini-BESTest changes were also evaluated in the two groups classified by the presence or absence of postural instability. One-way and two-way repeated measures analyses of variance were performed for each of the three periods of change, and paired t-tests with the Bonferroni method were performed as multiple comparison tests. A stepwise multiple regression model was used to identify factors associated with balance improvement. Results: A total of 60 patients with Parkinson's disease were included, and there were significant increases in Mini-BESTest, TIS, StrengthErgo240, and postural sway during closed-eye standing compared to pre- and postoperative conditions at discharge (p < 0.05), and they decreased significantly compared to the postoperative period (p < 0.05). On stepwise multiple regression analysis, decreased steps of TUG and improvement of TIS scores were related to improvement of the Mini-BESTest (p < 0.05). In addition, Mini-BESTest scores in both groups with and without postural instability were significantly increased at discharge compared to preoperative and postoperative conditions (p < 0.01). Conclusion: Postoperative rehabilitation combined with STN-DBS may provide short-term improvements in physical function compared with the preoperative medicated status. The improvements in gait step length and trunk function may be important factors for obtaining improvement of postoperative postural stability.

Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis.

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.

Potential Therapeutic Targets and Promising Agents for Combating NAFLD.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is a growing cause of liver cirrhosis and liver cancer worldwide because of the global increases in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. Contrary to the advancements in therapies for viral hepatitis, effective treatments remain unestablished for patients with NAFLD. NAFLD, including NASH, is characterized by steatosis, inflammation, hepatic necrosis, and fibrosis. Despite our understanding of its pathophysiology, there are currently no effective treatments for NAFLD. In this review, we provide an update on the known pathophysiological mechanisms involved in the development of NAFLD and the role of hepatic stellate cells, and summarize the potential therapeutic agents, including natural products, for NAFLD.

Loss of KAP3 decreases intercellular adhesion and impairs intracellular transport of laminin in signet ring cell carcinoma of the stomach.

Signet-ring cell carcinoma (SRCC) is a unique subtype of gastric cancer that is impaired for cell-cell adhesion. The pathogenesis of SRCC remains unclear. Here, we show that expression of kinesin-associated protein 3 (KAP3), a cargo adaptor subunit of the kinesin superfamily protein 3 (KIF3), a motor protein, is specifically decreased in SRCC of the stomach. CRISPR/Cas9-mediated gene knockout experiments indicated that loss of KAP3 impairs the formation of circumferential actomyosin cables by inactivating RhoA, leading to the weakening of cell-cell adhesion. Furthermore, in KAP3 knockout cells, post-Golgi transport of laminin, a key component of the basement membrane, was inhibited, resulting in impaired basement membrane formation. Together, these findings uncover a potential role for KAP3 in the pathogenesis of SRCC of the stomach.

Compassionate open-label use of rituximab following a randomised clinical trial against neuromyelitis optica (RIN-2 study): B cell monitoring-based administration.

OBJECTIVE: The aim of the RIN-2 study was a compassionate use of rituximab (RTX) for patients who completed the RIN-1 study, a multicentre, randomised, double-blind, placebo-controlled trial of RTX. We also investigated the long-term safety and efficacy of RTX. METHODS: A study design was a prospective open-label extension study following the RIN-1 study. RTX was infused repeatedly under monthly monitoring of CD19-positive and CD 20-positive B cell lymphocyte subsets from 24 weeks after an infusion. RESULTS: Thirty-three (87%) of 38 patients of the RIN-1 study were enrolled from February 2016 to March 2019 at six sites in Japan. In RIN-2, RTX was administered three times (median, range 1-5 times), and the interval of RTX administrations were 9.5 [2.5] months (mean [SD]). The observation period was 20.5 [10.1] months. During the trial, three patients dropped out due to two withdrawals and one adverse event. During the study, 28 (90%) of 31 patients were treated with RTX monotherapy. Neuromyelitis optica (NMO) relapses were observed in two patients. The annualized relapse rate (ARR) was 0.035 counts per person-years, ∼1/10th compared with 0.321 in the placebo arm of the RIN-1 study. We observed 14 severe adverse events in six (18%) and 156 adverse events, of which 135 were grade 1, 11 were grade 2 and 10 were grade 3. CONCLUSIONS: Under B cell monitoring, the interval of RTX re-infusion was elongated to nine months, and NMO relapses were suppressed with 0.035 of ARR.

White matter microstructures in Parkinson's disease with and without impulse control behaviors.

BACKGROUND: Impulse control behaviors (ICBs) in Parkinson's disease (PD) are thought to be caused by an overdose of dopaminergic therapy in the relatively spared ventral striatum, or by hypersensitivity of this region to dopamine. Alterations in brain networks are now also thought to contribute to the development of ICBs. OBJECTIVE: To comprehensively assess white matter microstructures in PD patients with ICBs using advanced diffusion MRI and magnetization transfer saturation (MT-sat) imaging. METHODS: This study included 19 PD patients with ICBs (PD-ICBs), 18 PD patients without ICBs (PD-nICBs), and 20 healthy controls (HCs). Indices of diffusion tensor imaging (DTI), diffusion kurtosis imaging, neurite orientation dispersion and density imaging, and MT-sat imaging were evaluated using tract-based spatial statistics (TBSS), regions of interest (ROIs), and tract-specific analysis (TSA). RESULTS: Compared with HCs, PD-nICBs had significant alterations in many major white matter tracts in most parameters. In contrast, PD-ICBs had only partial changes in several parameters. Compared with PD-ICBs, TBSS, ROI, and TSA analyses revealed that PD-nICBs had lower axial kurtosis, myelin volume fraction, and orientation dispersion index in the uncinate fasciculus and external capsule, as well as in the retrolenticular part of the internal capsule. These are components of the reward system and the visual and emotional perception areas, respectively. INTERPRETATION: Myelin and axonal changes in fibers related to the reward system and visual emotional recognition might be more prominent in PD-nICBs than in PD-ICBs.

Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents.

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.

Bortezomib is an effective enhancer for chemical probe-dependent superoxide detection.

Various chemical probes for the detection of reactive oxygen species have been developed to examine oxidative stress associated with different pathologies. L-012, a luminol-based chemiluminescent probe, is widely used to detect extracellular superoxide because of its high sensitivity. We herein demonstrated that the co-application of the peptide boronic acid proteasome inhibitor, bortezomib, with L-012 significantly increased its luminescence without affecting the background. More than a 5-fold increase was detected in the total luminescence of L-012 in both NADPH oxidase-expressing cells and the xanthine oxidase-dependent cell-free superoxide generation system, but not in their background. Therefore, bortezomib increased the signal-to-background ratio and improved the detection of low levels of superoxide. The application of MLN2238, another peptide boronic acid proteasome inhibitor, also enhanced the luminescence of L-012. In contrast, carfilzomib, an epoxyketone proteasome inhibitor, did not increase luminescence, suggesting that the effects of bortezomib depend on the chemical structure of the peptide boronic acid, but not on its pharmacological effects. Bortezomib-induced enhancements appeared to be specific to the detection of superoxide because the detection of H2O2 by Amplex Red/HRP was not affected by the application of bortezomib. In the quantitative detection of the superoxide-specific oxidative product 2-hydroxyethidium (2-OH-E+), the application of bortezomib resulted in a 2-fold increase in the level of 2-OH-E+. Therefore, bortezomib sensitizes the detection of superoxide in both cell-based and cell-free systems, highlighting a novel feature of compounds containing the peptide boronic acid as powerful enhancers for the detection of superoxide.

Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice.

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 ß-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.

TUBB3 E410K Syndrome With Childhood-Onset Nonalcoholic Steatohepatitis.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is becoming a major issue worldwide, even in children. Multiple parallel hits hypothesis has been suggested as progress of NAFLD, but the mechanism of NAFLD is not completely understood. ß-Tubulin is essential in mitoses, neuronal migration, and axon guidance during neuronal development. Pathogenic variants in the TUBB3 gene were shown to be associated with a wide spectrum of neurological abnormalities, but not accompanied by hepatic complications, such as NAFLD. OBJECTIVE: This work aims to examine the association between TUBB3 mutation and nonalcoholic steatohepatitis (NASH). METHODS: An 11-year-old girl has been followed up as having atypical Möbius syndrome since infancy, as she was born with bilateral ptosis, paralytic strabismus, and facial weakness. At age 7 years, she was diagnosed with TUBB3 E410K syndrome by whole-exome sequencing. At age 10 years, her blood examination revealed elevated liver transaminase levels, which persisted for almost 2 years. She underwent liver biopsy, the results of which were suggestive of NASH. RESULTS: The expression of TUBB3 was absent, but that of tyrosine hydroxylase (TH) was present in the parenchymal nerve fibers of the liver. On the other hand, in comparison with an autopsy case of NASH and a normal control, these showed coexpression of TUBB3 and TH in the liver. CONCLUSION: We report the first case of TUBB3 E410K syndrome accompanied by NASH. This case suggests that the TUBB3 mutation may be associated with the pathogenesis and progression of NASH in humans.