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Background: Hepatic steatosis and oxidative stress are considered to sequential steps in the development of non-alcoholic fatty liver disease (NAFLD). We previously found the protective effects of catalpol, an iridoid glucoside extracted from the root of Romania glutinosa L. Here, the increase expression of p66shc was found in NAFLD models and catalpol could inhibit p66shc expression ameliorating NAFLD effectively. Then, we investigated p66shc-targeting miRNAs in regulating oxidative stress and hepatic steatosis, and the potential role of p66shc in NAFLD. Methods: An NAFLD animal model established by low density lipoprotein receptor knockout (LDLr-/-) mice fed with high fat diet and cellular model by palmitic acid -treated hepG2 cells were employed to investigate the role of catalpol on NAFLD and the underling mechanism miR-96-5p involve in. With histological analysis, western blot, qPCR and transfection assay, identified miR-96-5p as being strongly differentially expressed between NAFLD and normal individuals and catalpol can ameliorate NAFLD via increasing miR-96-5p expression. Findings: We found that p66Shc, a protein induced by oxidative stress was significantly increased in NAFLD. Results also show that high level of p66shc is correlated with oxidative stress and hepatic steatosis. Moreover, targeting miR-96-5p by catalpol ameliorates oxidative stress and hepatic steatosis in LDLr-/- mice via p66shc/cytochrome C cascade. Interpretation: These data identify a role for miR-96-5p in NAFLD through inhibiting oxidative stress and hepatic steatosis via p66shc/cytochrome C cascade and the role of catalpol involve in. Funding Statement: This work was supported by grants from the Chinese National Natural Science Foundation (No.81273508). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: All experiments were approved by the Animal Care and Use Committee of Dalian Medical University, and the experimental procedures were performed in strict accordance with Legislation Regarding the Use and Care of Laboratory Animals of China.

Alcohol consumption is believed to involve genetic factors. In this paper genetically determined metabolic factors influencing the alcohol metabolism, such as different types of alcohol dehydrogenase and aldehyde dehydrogenase are discussed.

BACKGROUND Duct-to-duct biliary reconstruction has been increasingly used in living-donor liver transplantation. Information regarding dual duct-to-duct biliary anastomoses is limited. We present the largest case series to date on the use of the cystic and common hepatic ducts as dual-ductal anastomosis, along with long-term follow-up results. MATERIAL AND METHODS In this study, 740 patients underwent right-lobe living-donor liver transplantation; 56 of them were documented as dual-ductal anastomoses. We analyzed recipient and donor characteristics, surgical procedures, appearance of biliary complications, corresponding interventions, and long-term biliary outcomes. RESULTS Cystic and common hepatic ducts were utilized in 56 cases of dual-ductal biliary reconstruction, which we categorized into 2 types: A (78.6%), in which the right anterior intrahepatic duct was anastomosed to the common hepatic duct and the right posterior intrahepatic duct to the cystic duct; and B (21.4%), which was the reverse of A. After a median follow-up period of 46.4 months, 23 patients (41.1%) experienced complications, including biliary leakage and biliary stricture. However, after aggressive intervention (patent biliary anastomosis in most of them), 50 of 56 patients (89.3%) had patent biliary anastomosis and restored normal liver function at the end of follow-up. A small graft (graft-to-recipient weight ratio0.9%) was the only predictor of biliary complications after multivariate analysis. CONCLUSIONS Dual-ductal biliary reconstruction in adult right-lobe living-donor liver transplantation is challenging but feasible. Our findings support the use of the cystic duct for reconstruction in selected patients. Good long-term results can be achieved with adequate management of patients with biliary complications.

The occurrence of antituberculosis drug-induced liver injury affects the effectiveness of antituberculosis treatments. Understanding the mechanism and risk factors of such liver injury may improve the outcomes of those patients who received antituberculosis treatments. In this study, 2,255 pulmonary tuberculosis patients were included. Their medical records were reviewed, questionnaire surveys, liver function tests at the end of February (including patients with uncomfortable symptoms during the intensive treatment period), and blood samples were saved. Afterward, cases of liver damage were determined using Chinese liver damage criteria. The genotype of all participants was determined using the PCR-LDR method. Finally, the association between genetic polymorphism and ATB-DILI susceptibility was assessed using the univariate Logistic regression models. Among the 2,255 tuberculosis patients who received rifampicin, 612 (27.1%) had antituberculosis drug-induced liver injury. We observed higher proportions of older age, male, and lower levels of AST, ALT, and TBil among patients with liver injury. Results of univariate of logistic regression models showed that patients with CYP2C19 were more likely to have liver injury compared with no such genotypes patients (all P

Reduction of A. muciniphila relative abundance in the gut microbiota is a widely accepted signature associated with obesity-related metabolic disorders. Using untargeted metabolomics profiling of fasting plasma, our study aimed at identifying metabolic signatures associated with beneficial properties of alive and pasteurized A. muciniphila when administrated to a cohort of insulin-resistant individuals with metabolic syndrome. Our data highlighted either shared or specific alterations in the metabolome according to the form of A. muciniphila administered with respect to a control group. Common responses encompassed modulation of amino acid metabolism, characterized by reduced levels of arginine and alanine, alongside several intermediates of tyrosine, phenylalanine, tryptophan, and glutathione metabolism. The global increase in levels of acylcarnitines together with specific modulation of acetoacetate also suggested induction of ketogenesis through enhanced beta-oxidation. Moreover, our data pinpointed some metabolites of interest considering their emergence as substantial compounds pertaining to health and diseases in the more recent literature.

Objective: To evaluate time-dependent changes in hepatic extracellular volume (ECV) fraction using contrast-enhanced CT (CECT) and serological liver fibrosis markers, the fibrosis-4 (FIB-4) index and aspartate aminotransferase to platelet ratio index (APRI), before and after direct-acting antiviral therapy (DAA) for hepatitis C virus (HCV) infection. Methods: 41 HCV-infected patients who achieved sustained virological response (SVR) after DAA (SVR group) and 10 control patients (untreated or unresponsive to treatment) who underwent CECT and serum biochemical tests before or after the first examination/DAA (T1) and at intervals thereafter (T2:24 months) were evaluated. Results: In the control group, ECV fractions remained relatively unchanged through the study, and significant differences in FIB-4 index comparisons and APRI comparisons were only seen between the T2 and T4 values (p = 0.046 and p = 0.028, respectively). In the SVR group, ECV fractions were significantly different between T1 and T4 and T1 and T5 (p = 0.046 and 0.022, respectively), and both FIB-4 index and APRI were significantly different between T1 and all other time points (p = 0.017 to p < 0.001 and p = 0.001 to p < 0.001, respectively). Conclusion: After DAA, ECV fraction decreased slowly, suggesting an improvement in hepatic fibrosis, while serological liver fibrosis markers decreased immediately, probably due to improvement in hepatic inflammation. Advances in knowledge: ECV fraction has the potential to be a non-invasive biomarker for the assessment of liver fibrosis after direct-acting antiviral therapy.

Background & aims Plasma concentrations of bilirubin, a product of heme catabolism formed by biliverdin reductase A (BVRA), inversely associate with the risk of metabolic diseases including hepatic steatosis and diabetes mellitus in humans. Bilirubin has antioxidant and anti-inflammatory activities and may also regulate insulin signaling and peroxisome proliferator-activated receptor alpha (PPARα) activity. However, a causal link between bilirubin and metabolic diseases remains to be established. Here, we used the global Bvra gene knockout (Bvra–/–) mouse as a model of deficiency in bilirubin to assess its role in metabolic diseases. Approach & results We fed mice fat-rich diets to induce hepatic steatosis and insulin resistance. Bile pigments were measured by LC-MS/MS, and hepatic lipids by LC-MS/MS (non-targeted lipidomics), HPLC-UV and Oil-Red-O staining. Oxidative stress was evaluated measuring F2-isoprostanes by GC-MS. Glucose metabolism and insulin sensitivity were verified by glucose and insulin tolerance tests, ex vivo and in vivo glucose uptake, and Western blotting for insulin signaling. Compared with wild type littermates, Bvra–/– mice contained negligible bilirubin in plasma and liver, and they had comparable glucose metabolism and insulin sensitivity. However, Bvra–/– mice exhibited an inflamed and fatty liver phenotype, accompanied by hepatic accumulation of oxidized triacylglycerols and F2-isoprostanes, in association with depletion of α-tocopherol. α-Tocopherol supplementation reversed the hepatic phenotype and observed biochemical changes in Bvra–/– mice. Conclusions Our data suggests that BVRA deficiency renders mice susceptible to oxidative stress-induced hepatic steatosis in the absence of insulin resistance., Graphical abstract Image 1, Highlights • Low plasma levels of bilirubin associate with increased metabolic disease risk. • A direct link between bilirubin and metabolic disease remains to be established. • Global BVRA deficiency causes global bilirubin deficiency and a fatty, inflamed liver. • This hepatic phenotype is linked to decreased vitamin E and increased lipid oxidation. • Vitamin E supplements restore normal liver phenotype in BVRA deficiency.

NMR imaging of rats with implanted hepatomas in the liver demonstrates that under the imaging conditions of this study tumors of over 8 mm2 in area can be detected with high accuracy. Compared to normal liver, approximately 70% of these tumors had a combination of relaxation times (T1-T2) that could be uniquely identified as tumors, while the other 30% demonstrated relaxation time combinations that overlapped those previously found for abscesses, brain, and hematomas.

Timely detection of liver fibrosis by X‐ray computed tomography (CT) can prevent its progression to fatal liver diseases. However, it remains quite challenging because conventional CT can only identify the difference in density instead of X‐ray attenuation characteristics. Spectral CT can generate monochromatic imaging to specify X‐ray attenuation characteristics of the scanned matter. Herein, an X‐ray energy‐dependent attenuation strategy originated from bismuth (Bi)‐based nanoprobes (BiF3@PDA@HA) is proposed for the accurate diagnosis of liver fibrosis. Bi element in BiF3@PDA@HA can exhibit characteristic attenuation depending on different levels of X‐ray energy via spectral CT, and that is challenging for conventional CT. In this study, selectively accumulating BiF3@PDA@HA nanoprobes in the hepatic fibrosis areas can significantly elevate CT value for 40 Hounsfield units on 70 keV monochromatic images, successfully differentiating from healthy livers and achieving the diagnosis of liver fibrosis. Furthermore, the enhancement produced by the BiF3@PDA@HA nanoprobes in vivo increases as the monochromatic energy decreases from 70 to 40 keV, optimizing the conspicuity of the diseased areas. As a proof of concept, the strategically designed nanoprobes with energy‐dependent attenuation characteristics not only expand the scope of CT application, but also hold excellent potential for precise imaging‐based disease diagnosis., A strategy of energy‐dependent attenuation based on bismuth (Bi) nanomaterials is proposed. BiF3@PDA@HA nanoprobes accumulated in fibrosis‐afflicted areas can attenuate characteristically depending on monoenergetic X‐ray, further leading to fibrotic livers conspicuous via spectral computed tomography (CT). Yet conventional CT with polyenergetic X‐ray can't distinguish liver fibrosis from healthy liver.

This article also appears in: Health, Medical, and Life Sciences Virtual Issue for Advanced Science., Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype- and context-dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases., M.E. and J.G. were supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). A.B. was supported by an Australian Government Research Training Program (RTP) scholarship. E.B. was supported by Horizon 2020 under grant 634413 for the project EPoS.

Author(s): Kapre, Rohan; Zhou, Junhan; Li, Xinzhe; Beckett, Laurel; Louie, Angelique Y | Abstract: PurposeTo demonstrate that constant coefficient of variation (CV), but nonconstant absolute variance in MRI relaxometry (T1 , T2 , R1 , R2 ) data leads to erroneous conclusions based on standard linear models such as ordinary least squares (OLS). We propose a gamma generalized linear model identity link (GGLM-ID) framework that factors the inherent CV into parameter estimates. We first examined the effects on calculations of contrast agent relaxivity before broadening to other applications such as analysis of variance (ANOVA) and liver iron content (LIC).MethodsEightnmodels including OLS and GGLM-ID were initially fit to data obtained on sulfated dextran iron oxide (SDIO) nanoparticles. Both a resampling simulation on the data as well as two separate Monte Carlo simulations (with and without concentration error) were performed to determine mean square error (MSE) and type I error rate. We then evaluated the performance of OLS/GGLM-ID on R1 repeatability and LIC data sets.ResultsOLS had an MSE of 4-5× that of GGLM-ID as well as a type I error rate of 20-30%, whereas GGLM-ID was near the nominal 5% level in the relaxivity study. Only OLS found statistically significant effects of MRI facility on relaxivity in an R1 repeatability study, but no significant differences were found in a resampling, whereas GGLM was more consistent. GGLM-ID was also superior to OLS for modeling LIC.ConclusionsOLS leads to erroneous conclusions when analyzing MRI relaxometry data. GGLM-ID factors in the inherent CV of an MRI experiment, leading to more reproducible conclusions.

Objective: Studying the correlation of different lung parameters, using three-dimensional ultrasound (3D US) with fetal lung maturity (FLM) to predict the development of neonatal respiratory distress syndrome (RDS). Methods: Three-dimensional ultrasound was done to record the fetal lung volume (FLV), fetal lung-to-liver intensity ratio (FLLIR) and the main pulmonary artery (MPA) blood flow parameters; pulsatility index (PI), resistive index (RI) and acceleration time-to-ejection time ratio (At/Et), to 218 women between 32 and 40 weeks gestational age within 24 h from labor. Results: Of 218 fetuses examined, final analysis was done for 143 fetuses. Thirty eight (26.5%) were diagnosed with RDS. The MPA PI and RI were significantly higher in fetuses diagnosed with RDS compared with those without (2.51 ± 0.33 and 0.90 ± 0.03 cm/s versus 1.96 ± 0.20 and 0.84 ± 0.01 cm/s; p value < 0.001 and 3; p value < 0.001). Conclusion: Main pulmonary artery (PI, RI, At/Et ratio), FLIIR, and mean FLV can be used as reliable predictors of neonatal RDS. Advances in knowledge: 3D ultrasound VOCAL technique, ultrasound tissue histogram and pulmonary artery Doppler are reliable tools for prenatal prediction of fetal lung maturity.

Megaloblastic anemia (MA) patients often exhibit hemolysis, but it is not clear whether there are other hemolytic mechanisms in addition to intramedullary hemolysis. We retrospectively analyzed the clinical characteristics of 124 MA patients, measured erythrocyte physical parameters in two patients with hemolysis and one healthy volunteer by atomic force microscopy, and measured 18F-FDG uptake in one MA patient with hemolysis. In multivariate analysis, hemolysis was associated with mean corpuscular volume (MCV) and indirect bilirubin. A receiver operating characteristic curve analysis, with sensitivity of 83.1% and specificity of 68.7%, suggested that the MCV cutoff value that predicts hemolysis is 116.4 fL. Hb was negatively correlated with MCV in the hemolysis group (r = −0.317, P = 0.007) but not in the nonhemolysis group. The erythrocyte peak-valley value, average cell surface roughness and surface area in the MA patients with hemolysis were significantly lower than those in controls (P, GRAPHICAL ABSTRACT

BACKGROUND Dexmedetomidine (DEX) attenuates hepatic ischemia-reperfusion injury (HIRI) in adult liver transplantation (LT), but its effects on postoperative liver graft function in pediatric LT remain unclear. We sought to investigate whether intraoperative DEX administration was associated with improved liver graft function in pediatric LT recipients. It was hypothesized that DEX administration was associated with reduced HIRI and improved liver graft function. MATERIAL AND METHODS From November 2015 to May 2020, 54 deceased pediatric LT recipients were categorized into a control group and a DEX group. Intraoperatively, the DEX group received an additional infusion of DEX at 0.4 µg/kg/h from incision to the end of the operation in comparison with the control group. Preoperative, intraoperative, and postoperative data were reviewed. Postoperative liver enzyme levels and HIRI severity were assessed and compared. Independent risk factors for HIRI were determined by multivariate logistic regression analysis using a stepwise forward conditional method. RESULTS We enrolled 28 and 26 patients in the DEX and control groups, respectively. Patients in the DEX group exhibited a reduced incidence of moderate-to-severe HIRI (88.5% vs 60.7%, P=0.020) and decreased level of serum alanine aminotransferase (median [interquartile range]: 407 [230-826] vs 714 [527-1492] IU/L, P=0.048) compared with the controls. Binary logistic analysis revealed that longer cold ischemia time (odds ratio [OR]=1.006; 95% confidence interval [CI]=1.000-1.013; P=0.044) and intraoperative DEX use (OR=0.198; 95% CI=0.045-0.878; P=0.033) were independent predictors for moderate-to-severe HIRI. CONCLUSIONS Intraoperative low-dose DEX administration was associated with a lower incidence of moderate-to-severe HIRI in pediatric deceased LT. However, further studies are needed to confirm our results and elucidate the underlying mechanisms.

12/15-lipoxygenase (12/15-LOX) plays an essential role in oxidative conversion of polyunsaturated fatty acids into various bioactive lipid molecules. Although 12/15-LOX's role in the pathophysiology of various human diseases has been well studied, its role in weight gain is controversial and poorly clarified. Here, we demonstrated the role of 12/15-LOX in high-fat diet (HFD)-induced weight gain in a mouse model. We found that 12/15-LOX mediates HFD-induced de novo lipogenesis (DNL), triglyceride (TG) biosynthesis and the transport of TGs from the liver to adipose tissue leading to white adipose tissue (WAT) expansion and weight gain via xanthine oxidase (XO)-dependent production of H2O2. 12/15-LOX deficiency leads to cullin2-mediated ubiquitination and degradation of XO, thereby suppressing H2O2 production, DNL and TG biosynthesis resulting in reduced WAT expansion and weight gain. These findings infer that manipulation of 12/15-LOX metabolism may manifest a potential therapeutic target for weight gain and obesity., Highlights • 12/15-LOX-12(S)-HETE axis via activation of CREB-Egr1 enhances TG biosynthesis. • 12/15-LOX-12(S)-HETE axis via activation of SREBP1c triggers DNL. • H2O2 mediates 12/15-LOX-12(S)-HETE axis-induced DNL and TG biosynthesis. • 12/15-LOX via TG biosynthesis leads to WAT expansion and body weight gain. • Downstream to 12/15-LOX, H2O2-mediates WAT expansion and body weight gain.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60–77 years, with 12–53% overall adiposity (BMI of 17.8–46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.

Aging, like obesity, is associated with metabolic and inflammatory alterations within adipose tissue in older individuals. Younger females are protected from adipose inflammation, but older post-menopausal females exhibit exaggerated visceral adiposity correlated with increased disease risk. Obesity accelerates the onset and progression of age-associated diseases, but it is unclear if aging and obesity drive adipose tissue dysfunction in a sexually dimorphic fashion. We investigated adipose tissue metabolism and inflammation in a diet-induced obesity model in young and old mice. We identified age related sex differences in adipose tissue macrophages (ATMs), fibrosis and lipid metabolism in male and female visceral fat depot (GWAT). Although aging normalized body weights between the sexes, females remained protected from proinflammatory ATMs and stimulated lipolysis failed to adversely affect the inflammatory state even with obesity. Older obese males had augmented CD11c+ ATMs and higher insulin levels, while females showed increased visceral adiposity and exaggerated Pparγ, and Pgc1α expression. Obesity in aging demonstrated similar expression of GWAT p53, p16, p21, Timp1 and Tgfβ1 in both sexes. Our studies suggest that even with aging, female GWAT shows an attenuated inflammatory response compared to males due to an efficient oxidative metabolism combined with an active tissue remodeling state.

Several signaling pathways may be affected during aging. All are regulated by nutrient levels leading to a decline in mitochondrial function and autophagy and to an increase in oxidative stress. PAS Domain Kinase (PASK) is a nutrient and bioenergetic sensor. We have previously found that PASK plays a role in the control of hepatic metabolic balance and mitochondrial homeostasis. To investigate PASK’s role in hepatic oxidative stress during aging, we analyzed the mitochondrial function, glucose tolerance, insulin resistance, and lipid-related parameters in aged PASK-deficient mice. Hepatic Pask mRNA decreased in step with aging, being undetectable in aged wild-type (WT) mice. Aged PASK-deficient mice recorded lower levels of ROS/RNS compared to aged WT. The regulators of mitochondrial biogenesis, PGC1a, SIRT1 and NRF2, decreased in aged WT, while aged PASK-deficient mice recorded a higher expression of NRF2, GCLm and HO1 proteins and CS activity under fasted conditions. Additionally, aged PASK-deficient mice recorded an overexpression of the longevity gene FoxO3a, and maintained elevated PCNA protein, suggesting that hepatic cell repair mechanisms might be functional. PASK-deficient mice have better insulin sensitivity and no glucose intolerance, as confirmed by a normal HOMA-IR index. PASK may be a good target for reducing damage during aging.

Flavin-containing monooxygenase 3 (FMO3) gene expression is often upregulated in long-lived murine models. However, the specific relationship between FMO3 and aging remains unknown. Here, we show that 40% calorie restriction (CR), which is considered to be one of the most robust interventions to delay aging progression, markedly upregulates FMO3. Most importantly, upregulation of hepatocyte FMO3 in murine models prevented or reversed hepatic aging. Accordingly, the upregulation of FMO3 mimicked the effects of CR: reduced serum levels of pro-inflammatory cytokine interleukin-6 and fasting insulin; relief of oxidative stress, with lower hepatic malondialdehyde levels and higher superoxide dismutase activity; reduced serum and hepatic levels of total cholesterol and triglyceride, as well as reduced lipid deposition in the liver; and diminished levels of aging-related markers β-gal and p16. There were also synergistic effects between FMO3 upregulation and CR. Inhibition of autophagy blocked the anti-aging effects of upregulation of hepatocyte FMO3, including reversing the amelioration of the serum and hepatic parameters related to inflammation, oxidative stress, lipid metabolism, liver function, and hepatocyte senescence. Our results suggest that the upregulation of FMO3 mimics CR to prevent or reverse hepatic aging by promoting autophagy.

Rationale: RNA helicase DDX5 is downregulated during hepatitis B virus (HBV) replication, and poor prognosis HBV-related hepatocellular carcinoma (HCC). The aim of this study is to determine the mechanism and significance of DDX5 downregulation for HBV-driven HCC, and identify biologics to prevent DDX5 downregulation. Methods: Molecular approaches including immunoblotting, qRT-PCR, luciferase transfections, hepatosphere assays, Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), and RNA-seq were used with cellular models of HBV replication, HBV infection, and HBV-related liver tumors, as well as bioinformatic analyses of liver cancer cells from two independent cohorts. Results: We demonstrate that HBV infection induces expression of the proto-oncogenic miR17~92 and miR106b~25 clusters which target the downregulation of DDX5. Increased expression of these miRNAs is also detected in HBV-driven HCCs exhibiting reduced DDX5 mRNA. Stable DDX5 knockdown (DDX5KD) in HBV replicating hepatocytes increased viral replication, and resulted in hepatosphere formation, drug resistance, Wnt activation, and pluripotency gene expression. ATAC-seq of DDX5KD compared to DDX5 wild-type (WT) cells identified accessible chromatin regions enriched in regulation of Wnt signaling genes. RNA-seq analysis comparing WT versus DDX5KD cells identified enhanced expression of multiple genes involved in Wnt pathway. Additionally, expression of Disheveled, DVL1, a key regulator of Wnt pathway activation, was significantly higher in liver cancer cells with low DDX5 expression, from two independent cohorts. Importantly, inhibitors (antagomirs) to miR17~92 and miR106b~25 restored DDX5 levels, reduced DVL1 expression, and suppressed both Wnt activation and viral replication. Conclusion : DDX5 is a negative regulator of Wnt signaling and hepatocyte reprogramming in HCCs. Restoration of DDX5 levels by miR17~92 / miR106b~25 antagomirs in HBV-infected patients can be explored as both antitumor and antiviral strategy.

Rationale: Light pollution leads to high risk of obesity but the underlying mechanism is not known except for the influence of altered circadian rhythm. Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, but its role in circadian-related obesity is not clear. Methods: Wild-type (WT) and Ppara-null (KO) mice on a high-fat diet (HFD) were treated with neon light at night for 6 weeks. Body weights were recorded and diet consumption measured. The hypothalamus, liver, adipose and serum were collected for mechanism experimentation. Results: WT mice on a HFD and exposed to night neon light gained about 19% body weight more than the WT control mice without light exposure and KO control mice on a HFD and exposed to night neon light. The increase in adipose tissue weight and adipocyte size led to the differences in body weights. Biochemical analysis suggested increased hepatic lipid accumulated and increased transport of lipid from the liver to peripheral tissues in the WT mice that gained weight under neon light exposure. Unlike KO mice, the expression of genes involved in lipid metabolism and the circadian factor circadian locomotor output cycles kaput (CLOCK) in both liver and adipose tissues were elevated in WT mice under neon light exposure. Conclusions: PPARα mediated weight gain of HFD-treated mice exposed to night neon light. More lipids were synthesized in the liver and transported to peripheral tissue leading to adaptive metabolism and lipid deposition in the adipose tissue. These data revealed an important mechanism of obesity induced by artificial light pollution where PPARα was implicated.

Introduction: This study was designed to assess the effect of repetitive exposure to intravenous anesthetic agents on the immunity in mice. Materials and Methods: The mice were divided into six groups: three intravenous anesthetic agents groups (dexmedetomidine, midazolam and propofol groups), and three corresponding control groups (CD, CM, and CP groups). The intravenous injections were administered once per day for 5 days. The immunity of mice was checked after the last intravenous injection. Histopathology and immunochemistry of liver and kidneys were evaluated. Cytokine levels in the blood was also checked. vs. evaluated with cytokine levels in the blood. Results: Cluster of differentiation (CD)4+ T cells were significantly less expressed in dexmedetomidine and propofol groups, compared with the corresponding control groups [34.08 ± 5.63% in the dexmedetomidine group vs. 59.74 ± 8.64% in the CD group, p < 0.05; 25.28 ± 7.28% in the propofol group vs. 61.12 ± 2.70% in the Cp group, p < 0.05]. Apoptosis of CD4+ T cells was increased significantly in dexmedetomidine and propofol groups, compared with the corresponding control groups. Histopathological findings of liver and kidneys did not show any specific differences of any of three intravenous anesthetic agents groups with their corresponding control groups, although immunohistochemical examination indicated significantly lower expression of Toll-like receptor-4 from liver and kidneys in dexmedetomidine and propofol groups. The cytokine levels were not different between the groups. Conclusion: Repetitive exposure to dexmedetomidine and propofol reduced the expression of CD4+ T cells but did not induce any significant liver or kidney injuries.

Four commonly used organophosphates (fenitrothion, dichlorvos, chlorpyrifos, and trichlorfon) were orally administered to male Sprague-Dawley rats for five days in order to explore their effects on the activities of liver cytochrome P450 (CYP). In addition, Michaelis-Menten kinetics of the metabolic reactions catalyzed by liver CYPs were analyzed following the addition of these compounds to the assay system to examine their potential inhibitory effects on liver CYPs activities. These reactions included ethoxyresorufin O-deethylation, midazolam 4-hydroxylation, tolbutamide hydroxylation, and bufuralol 1’-hydroxylation for CYP1A, 3A, 2C, and 2D activities, respectively. Total CYP content was also examined after oral administration of each organophosphate. Results revealed that oral giving of fenitrothion inhibited significantly CYP1A and 3A activities while elevated activity of CYP2C. Fenitrothion is a potent inhibitor for CYP1A and 2C with Ki values of 0.42 and 36.1 µM, respectively but had a weak inhibitory effect on CYP2D and 3A with Ki values of 290 and 226 µM, respectively. Chlorpyrifos is a potent inhibitor of CYP1A with Ki 0.24 µM and moderately inhibited CYP2C or 3A with Ki values of 84.8 and 77.7 µM, respectively. On the other hand, dichlorvos and trichlorfon caused extremely low or negligible inhibition of different CYP activities. From these results, it is concluded that both fenitrothion and chlorpyrifos may increase the toxicity of chemicals in environmental living organisms through their potent inhibitory effects on these CYP activities, but dichlorvos and trichlorfon may not.

Objective: Type 2 diabetes mellitus (T2DM) is a chronic condition resulting from insulin resistance and insufficient β-cell secretion, leading to improper glycaemic regulation. Previous studies have found that excessive fat deposits in organs such as the liver and muscle can cause insulin resistance through lipotoxicity that affects β-cell function. The relationships between fat deposits in pancreatic tissue, the function of β-cells, the method of visceral fat evaluation and T2DM have been sought by researchers. This study aims to elucidate the role of pancreatic fat deposits in the development of T2DM using quantitative computed tomography (QCT), especially their effects on islet β-cell function. Methods: We examined 106 subjects at the onset of T2DM who had undergone abdominal QCT. Estimated pancreatic fat and liver fat were quantified using QCT and calculated. We analysed the correlations with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores and other oral glucose tolerance test-derived parameters that reflect islet function. Furthermore, correlations of estimated pancreatic fat and liver fat with the area under the curve for insulin (AUCINS) and HOMA-IR were assessed with partial correlation analysis and demonstrated by scatter plots. Results: Associations were found between estimated liver fat and HOMA-IR, AUCINS, the modified β-cell function index (MBCI) and Homeostatic Model Assessment β (HOMA-β). However, no significant differences existed between estimated pancreas fat and those parameters. Similarly, after adjustment for sex, age and body mass index, only estimated liver fat was correlated with HOMA-IR and AUCINS. Conclusions: This study suggests no significant correlation between pancreatic fat deposition and β-cell dysfunction in the early stages of T2DM using QCT as a screening tool. The deposits of fat in the pancreas and the resulting lipotoxicity may play an important role in the late stage of islet cell function dysfunction as the course of T2DM progresses.

A coronary heart disease leads to increase in obesity and metabolic dysfunction. Protocatechuic acid (PCA), due to its antioxidant, anti-inflammatory, neuro protective activities was found efficient as cardio-protective in coronary heart disease. Our study investigated hypolipidemic and cardioprotective effects of protocatechuic acid in the coronary artery disease induced by high fat and fructose diet (HFD) rat models. A diet rich in fat and fructose was fed to male Wistar rats prior to the start of experimental procedures. Serum lipid levels and hepatic triglycerides (TG) and total cholesterol (TC) levels were examined and analyzed. Both in vitro an in vivo pancreatic lipase activity was determined as well. Histopathological examination was performed and their results were noted. Noteworthy reduction of serum lipid levels and hepatic TG and TC levels was seen in groups treated with simvastatin (SIM; 20 mg/kg) and PCA (50 and 100 mg/kg) in comparison to HFD groups. Pancreatic lipase activity was reduced in the SIM group and the group treated with doses of PCA (50 and 100 mg/kg). A marked increase in gain in body weight per week (P

Purpose: Hepatobiliary-phase (HBP) MRI with gadoxetic acid facilitates the differentiation between lesions with and without functional hepatocytes. Thus, high-quality HBP images are required for the detection and evaluation of hepatic lesions. However, the long scan time may increase artifacts due to intestinal peristalsis, resulting in the loss of diagnostic information. Pseudo-random acquisition order disperses artifacts into the background. The aim of this study was to investigate the clinical applicability of pseudo-random trajectory scanning for the suppression of motion artifacts on T1-weighted images including HBP. Methods: Our investigation included computer simulation, phantom experiments, and a clinical study. For computer simulation and phantom experiments a region of interest (ROI) was placed on the area with motion artifact and the standard deviation inside the ROI was measured as image noise. For clinical study we subjected 62 patients to gadoxetic acid-enhanced hepatobiliary-phase imaging with a circular- and a pseudo-random trajectory (c-HBP and p-HBP); two radiologists graded the motion artifacts, sharpness of the liver edge, visibility of intrahepatic vessels, and overall image quality using a five-point scale where 1 = unacceptable and 5 = excellent. Differences in the qualitative scores were determined using the two-sided Wilcoxon signed-rank test. Results: The image noise was higher on the circular image compared with pseudo-random image (101.0 vs 60.9 on computer simulation image, 91.2 vs 67.7 on axial, 95.5 vs 86.9 on reformatted sagittal image for phantom experiments). For clinical study the score for motion artifacts was significantly higher with p-HBP than c-HBP imaging (left lobe: mean 3.4 vs 3.2, P < 0.01; right lobe: mean 3.6 vs 3.4, P < 0.01) as was the qualitative score for the overall image quality (mean 3.6 vs 3.3, P < 0.01). Conclusion: At gadoxetic acid-enhanced hepatobiliary-phase imaging, p-HBP scanning suppressed motion artifacts and yielded better image quality than c-HBP scanning.

Interleukin (IL)-19 is a cytokine clustered in the IL-20 cytokine superfamily with both anti-inflammatory and pro-inflammatory aspects depending on the etiology of inflammatory disease. The function of IL-19 has been evaluated in cutaneous and inflammatory bowel diseases, but has not been studied in liver diseases. Here, we examined the effect of IL-19 on acute liver failure (ALF) using two mouse models of ALF: lipopolysaccharide and D-galactosamine (LPS/GalN)-induced model and concanavalin A (ConA)-induced model. In the LPS/GalN-induced ALF model, which is mainly caused by the innate immune response of liver macrophages, IL-19 knockout (KO) mice showed increased plasma level of liver deviation enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) compared with wild-type (WT) mice. In histopathology of liver sections, IL-19 KO mice exacerbated liver injury with marked hemorrhagic lesions and hepatocellular death in the liver compared with WT mice. In this model, mRNA expressions of pro-inflammatory chemokines, CCL2 and CCL5 were increased in liver tissue from IL-19 KO mice compared with WT mice. Moreover, the mRNA expressions of IL-19 and its receptor subunit were induced in liver tissue by LPS/GalN administration. However, there is no difference in liver injury between WT and IL-19KO in the ConA-induced ALF model induced by CD4+ T cell activation. These data suggest that IL-19 has a protective effect against inflammation-mediated liver injury, which is dependent on the etiology.

Instantaneous blood coagulation after bioengineered liver transplantation is a major issue, and the key process in its prevention is the construction of the endothelial vascular bed on biomimetic scaffolds. However, the specific molecules involved in the regulation of the vascular bed formation remain unclear. Syndecan-4 is a type I transmembrane glycoprotein commonly expressed in the human body; its receptor has been reported as critical for optimal cell adhesion and initiation of intracellular signaling, indicating its promising application in vascular bed formation. In the current study, bioinformatics analysis and in vitro experiments were performed to evaluate whether syndecan-4 promoted endothelial cell migration and functional activation. Exogenous syndecan-4-overexpressing endothelial cells were perfused into the decellularized liver scaffold, which was assessed by Masson’s trichrome staining. Western blotting and qRT-PCR were used to evaluate the effects of syndecan-4 on the thrombospondin 1 (THBS1) stability. We found that syndecan-4 promoted the adhesion of vascular endothelial cells and facilitated cell migration and angiogenesis. Furthermore, syndecan-4 overexpression resulted in a well-aligned endothelium on the decellularized liver scaffolds. Mechanistically, syndecan-4 destabilized THBS1 at the protein level. Therefore, our data revealed that syndecan-4 promoted the biological activity of endothelial cells on the bionic liver vascular bed through THBS1. These findings provide scientific evidences for solving transient blood coagulation after bionic liver transplantation., Graphical abstract

Müller glia are specialized retinal cells with stem cell properties in fish and frogs but not in mammals. Current efforts to develop gene therapies to activate mammalian Müller glia for retinal repair will require safe and effective delivery strategies for recombinant adeno-associated viruses (AAVs), vectors of choice for clinical translation. Intravitreal and subretinal injections are currently used for AAV gene delivery in the eye, but less invasive methods efficiently targeting Müller glia have yet to be developed. Methods: As gene delivery strategies have been more extensively studied in the brain, to validate our vectors, we initially compared the glial tropism of AAV-PHP.eB, an AAV9 that crosses the blood-brain and blood-retinal barriers, for its ability to drive fluorescent protein expression in glial cells in both the brain and retina. We then tested the glial transduction of AAV2/8-GFAP-mCherry, a virus that does not cross blood-brain and blood-retinal barriers, for its effectiveness in transducing Müller glia in murine retinal explants ex vivo. For in vivo assays we used larger rat eyes, performing invasive intravitreal injections, and non-invasive intravenous delivery using focused ultrasound (FUS) (pressure amplitude: 0.360 - 0.84 MPa) and microbubbles (Definity, 0.2 ml/kg). Results: We showed that AAV-PHP.eB carrying a ubiquitous promoter (CAG) and green fluorescent protein (GFP) reporter, readily crossed the blood-brain and blood-retinal barriers after intravenous delivery in mice. However, murine Müller glia did not express GFP, suggesting that they were not transduced by AAV-PHP.eB. We thus tested an AAV2/8 variant, which was selected based on its safety record in multiple clinical trials, adding a glial fibrillary acidic protein (GFAP) promoter and mCherry (red fluorescent protein) reporter. We confirmed the glial specificity of AAV2/8-GFAP-mCherry, showing effective expression of mCherry in astrocytes after intracranial injection in the mouse brain, and of Müller glia in murine retinal explants. For in vivo experiments we switched to rats because of their larger size, injecting AAV2/8-GFAP-mCherry intravitreally, an invasive procedure, demonstrating passage across the inner limiting membrane, leading to Müller glia transduction. We then tested an alternative non-invasive delivery approach targeting a different barrier - the inner blood-retinal-barrier, applying focused ultrasound (FUS) to the retina after intravenous injection of AAV2/8 and microbubbles in rats, using magnetic resonance imaging (MRI) for FUS targeting. FUS permeabilized the rat blood-retinal-barrier and allowed the passage of macromolecules to the retina (Evans blue, IgG, IgM), with minimal extravasation of platelets and red blood cells. Intravenous injection of microbubbles and AAV2/8-GFAP-mCherry followed by FUS resulted in mCherry expression in rat Müller glia. However, systemic delivery of AAV2/8 also had off-target effects, transducing several murine peripheral organs, particularly the liver. Conclusions: Retinal permeabilisation via FUS in the presence of microbubbles is effective for delivering AAV2/8 across the inner blood-retinal-barrier, targeting Müller glia, which is less invasive than intravitreal injections that bypass the inner limiting membrane. However, implementing FUS in the clinic will require a comprehensive consideration of any off-target tropism of the AAV in peripheral organs, combined ideally, with the development of Müller glia-specific promoters.

This study investigated the use of transient elastography (TE) as a tool for the non-invasive evaluation of liver stiffness and controlled attenuation parameter (CAP) in cows. A total of 85 cows were used for this study. After the liver was located and subcutaneous tissue thickness was checked by means of ultrasonography, liver stiffness and CAP were measured using TE. At least 10 measurements were taken per individual cow. In addition, intraclass correlation coefficients were calculated for intra-rater and two-rater inter-rater reliability of liver stiffness and CAP measurement, and were evaluated. Of the 85 cows, 61 (71.8%) were measurable owing to their significantly less body weight and subcutaneous tissue thickness compared with those of unmeasurable cows. Liver stiffness showed no significant differences among sexes, ages, or breeds. CAP showed no significant differences among sexes and breeds. Intra- and inter-rater reliabilities for liver stiffness and CAP were almost perfect. Both liver stiffness and CAP could be quantitatively evaluated with good reproducibility in cows using TE, and CAP increased with the growth of the cows. However, evaluation was not possible in obese cows or cows with high values for subcutaneous tissue thickness or body weight.

We investigated changes in peripheral blood metabolites, oxidative stress markers (malondialdehyde, potential antioxidant capacity, and glutathione peroxidase [GPX]), and hepatic gene expression related to oxidative stress in Holstein cows with and without subacute ruminal acidosis (SARA) during the periparturient period. Eighteen multiparous Holstein cows were categorized into SARA (n=9) or non-SARA (n=9) groups depending on whether they developed SARA; reticulo-ruminal pH was

Hypercholesterolemia is a major risk factor for several cardiovascular and metabolic diseases as it triggers oxidative and pro-inflammatory cascades. Baicalein (BL) is a natural flavone with multiple therapeutic properties. The present study aimed to evaluate the potential protective effect of BL supplementation in hypercholesterolaemic rats. Rats were fed a high-cholesterol diet (HCD) for six weeks and then orally administered BL at two doses (25 and 50 mg/kg body weight/day) for four weeks. Serum lipids, liver enzymes, cardiac enzymes, renal markers, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), interleukin-10 (IL-10), caspase-3, nitric oxide (NO) and prostaglandin-2 (PGE-2) were measured. In renal, hepatic, and cardiac tissues, thiobarbituric acid-reactive (TBARS) substance, glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were measured. The altered levels of lipoproteins, aminotransferases, creatine kinases, and urea in hypercholesterolemic animals were significantly corrected by BL. Inflammatory and apoptotic biomarkers were also markedly attenuated in the HCD group following BL treatment. Hypercholesterolemia considerably induced the lipid peroxidation product, TBARS, and oxidative radicals in cardiac, hepatic, and renal tissues, which were attenuated by BL treatment, particularly, at the 50 mg/kg/day dose. BL enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase that were suppressed by HCD. Histological alterations induced by cholesterol overload in cardiac, hepatic, and renal tissues were ameliorated by BL supplementation. Our results show that the BL treatments (25 and 50 mg/kg/day) to HCD fed rats improved all the altered parameters. These results demonstrate that BL treatment improves cardiac, renal and hepatic dysfunctions in hypercholesterolaemic rats by activation of cellular antioxidant enzymes and/or suppression of inflammatory cytokines.

Emerging evidence suggests that long non-coding RNAs (lncRNA) play critical roles in the development and progression of diverse cancers including hepatocellular carcinoma (HCC), but the underlying molecular mechanisms of lncRNAs that are involved in hepatocarcinogenesis have not been fully explored. Methods: In this study, we profiled lncRNA expression in 127 pairs of HCC and nontumor liver tissues (a Discovery Cohort) using a custom microarray. The expression and clinical significance of lncCSMD1-1 were then validated with qRT-PCR and COX regression analysis in a Validation Cohort (n=260) and two External Validation Cohorts (n=92 and n=124, respectively). In vitro and in vivo assays were performed to explore the biological effects of lncCSMD1-1 on HCC cells. The interaction of lncCSMD1-1 with MYC was identified by RNA pull-down and RNA immunoprecipitation. The role of LncCSMD1-1 in the degradation of MYC protein was also investigated. Results: With microarray, we identified a highly upregulated lncRNA, lncCSMD1-1, which was associated with tumor progression and poor prognosis in the Discovery Cohort, and validated in another 3 HCC cohorts. Consistently, ectopic expression of lncCSMD1-1 notably promotes cell proliferation, migration, invasion, tumor growth and metastasis of HCC cells in in vitro and in vivo experiments. Gene expression profiling on HCC cells and gene sets enrichment analysis indicated that the MYC target gene set was significantly enriched in HCC cells overexpressing lncCSMD1-1, and lncCSMD1-1 was found to directly bind to MYC protein in the nucleus of HCC cells, which resulted in the elevation of MYC protein. Mechanistically, lncCSMD1-1 interacted with MYC protein to block its ubiquitin-proteasome degradation pathway, leading to activation of its downstream target genes. Conclusion: lncCSMD1-1 is upregulated in HCC and promotes progression of HCC by activating the MYC signaling pathway. These results provide the evidence that lncCSMD1-1 may serve as a novel prognostic marker and potential therapeutic target for HCC.

Acute liver failure is characterized by the rapid development of liver dysfunction and remarkably high mortality. Accumulating evidence suggests that soyasaponin possesses potential anti-inflammatory activities. Here, we aimed to investigate the potential role of soyasaponin II in acute liver failure and establish the underlying mechanism. Methods: Lipopolysaccharide/D-galactosamine (LPS/GalN) was employed to induce acute liver failure. We applied liquid chromatography and mass spectrometry (LC/MS) to characterize the changes of soyasaponin II levels in the cecal content and liver. Transcriptomics and proteomics analysis were used to evaluate the functional molecule mediated by soyasaponin II in macrophages. Results: LPS/GalN administration markedly decreased fecal and hepatic soyasaponin II levels. Soyasaponin II treatment protected mice against LPS/GalN induced acute liver injury. Additionally, soyasaponin II markedly diminished Y-Box Binding Protein 1 (YB-1) phosphorylation and nuclear translocation, Nlrp3 inflammasome priming, and interleukin 1β (Il-1β) production in macrophages. Phosphorylated YB-1 could activate Nlrp3 mRNA transcription by binding the promoter region. Finally, immunofluorescence analysis showed elevated p-YB-1 nuclear translocation in macrophages of acute liver failure patients compared to controls. Conclusion: Our data shows that soyasaponin II which serves as a novel inhibitor for YB-1 phosphorylation and Nlrp3 inflammasome priming could protect mice against LPS/GalN induced acute liver failure.

Rationale: Men and postmenopausal women are more prone to developing non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) than premenopausal women. However, the pathological links and underlying mechanisms of this disparity are still elusive. The sex-difference in hepatic very low-density lipoprotein (VLDL) assembly and secretion may contribute to NAFLD development. Estrogen-related receptor alpha (ERRα) is a key regulator of several metabolic processes. We hypothesized that ERRα plays a role contributing to the sex-difference in hepatic VLDL assembly and secretion. Methods: VLDL secretion and essential genes governing said process were assessed in male and female mice. Liver-specific ERRα-deficient (ERRαLKO) mice were generated to assess the rate of hepatic VLDL secretion and alteration in target gene expression. Overexpression of either microsomal triglyceride transfer protein (Mttp) or phospholipase A2 G12B (Pla2g12b) by adenovirus was performed to test if the fatty liver phenotype in male ERRαLKO mice was due to defects in hepatic VLDL secretion. Female ERRαLKO mice were put on a diet high in saturated fat, fructose and cholesterol (HFHC) to promote NASH development. Wild type female mice were either ovariectomized or treated with tamoxifen to induce a state of estrogen deficiency or disruption in estrogen signaling. Adenovirus was used to overexpress ERRα in these mice to test if ERRα was sufficient to rescue the suppressed VLDL secretion due to estrogen dysfunction. Finally, wild type male mice on a high-fat diet (HFD) were treated with an ERRα inverse agonist to assess if suppressing ERRα activity pharmacologically would lead to fatty liver development. Results: ERRα is an indispensable mediator modulating hepatic triglyceride-rich very low-density lipoprotein (VLDL-TG) assembly and secretion through coordinately controlling target genes apolipoprotein B (Apob), Mttp and Pla2g12b in a sex-different manner. Hepatic VLDL-TG secretion is blunted in ERRαLKO mice, leading to hepatosteatosis which exacerbates endoplasmic reticulum stress and inflammation paving ways for NASH development. Importantly, ERRα acts downstream of estrogen/ERα signaling in contributing to the sex-difference in hepatic VLDL secretion effecting hepatic lipid homeostasis. Conclusions: Our results highlight ERRα as a key mediator which contributes to the sex disparity in NAFLD development, suggesting that selectively restoring ERRα activity in the liver may be a novel strategy for treating NAFLD/NASH.