Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.

Joint Association of Metabolic Health and Obesity with Ten-Year Risk of Cardiovascular Disease among Chinese Adults

Objective This study aims to investigate the association of metabolic phenotypes that are jointly determined by body mass index(BMI)or fat mass percentage and metabolic health status with the tenyear risk of cardiovascular disease(CVD)among Chinese adults.Methods Data were obtained from a cross-sectional study.BMI and body fat mass percentage(FMP)combined with the metabolic status were used to define metabolic phenotypes.Multiple linear regression and logistic regression were used to examine the effects of metabolic phenotypes on CVD risk.Results A total of 13,239 adults aged 34-75 years were included in this study.Compared with the metabolically healthy non-obese(MHNO)phenotype,the metabolically unhealthy non-obese(MUNO)and metabolically unhealthy obese(MUO)phenotypes defined by BMI showed a higher CVD risk[odds ratio,OR(95% confidence interval,CI):2.34(1.89-2.89),3.45(2.50-4.75),respectively],after adjusting for the covariates.The MUNO and MUO phenotypes defined by FMP showed a higher CVD risk[OR(95%CI):2.31(1.85-2.88),2.63(1.98-3.48),respectively]than the MHNO phenotype.The metabolically healthy obese phenotype,regardless of being defined by BMI or FMP,showed no CVD risk compared with the MHNO phenotype.Conclusion General obesity without central obesity does not increase CVD risk in metabolically healthy individuals.FMP might be a more meaningful factor for the evaluation of the association of obesity with CVD risk.Obesity and metabolic status have a synergistic effect on CVD risk.

Shifting perspectives-interplay between non-alcoholic fatty liver disease and insulin resistance in lean individuals

Non-alcoholic fatty liver disease(NAFLD)has become a significant public health burden affecting not only obese individuals but also people with normal weight.As opposed to previous beliefs,this particular subset of patients has an increased risk of all-cause mortality and worse outcomes than their obese counterparts.The development of NAFLD in lean subjects seems to be interconnected with metabolic phenotype,precisely visceral fat tissue,sarcopenia,and insulin resistance.Here,we summarize available data focusing on the co-dependent relationship between metabolic phenotype,insulin resistance,and development of NAFLD in lean individuals,suggesting more appropriate tools for measuring body fat distribution for the screening of patients at risk.

Elementary Flux Mode Analysis for Optimized Ethanol Yield in Anaerobic Fermentation of Glucose with Saccharomyces cerevisiae

Elementary flux mode （EFM） analysis was used in the metabolic analysis of central carbon metabolism in Saccharomyces cerevisiae based on constructed cellular network. Calculated from the metabolic model, the ethanol-producing pathway No. 37 furthest converts the substrate into ethanol among the 78 elementary flux modes. The in silico metabolic phenotypes predicted based on this analysis fit well with the fermentation performance of the engineered strains, KAM3 and KAMll, which confirmed that EFM analysis is valid to direct the construction of Saccharomyces cerevisiae engineered strains, to increase the ethanol yield.

In vitro metabolism and inhibitory effects of atractylenolideⅡon various hepatic CYPs in HLMs

In the present study,we aimed to investigate the interaction between atractylenolideⅡ(AT-Ⅱ)and CYP450 enzyme in human liver microsomes,and to lay a theoretical foundation for predicting the possible interaction of AT-Ⅱin combination with drugs.The chemical inhibition experiment was carried out with specific inhibitors to clarify the CYP450 subtypes affecting the metabolism of AT-Ⅱ,and the mechanism,kinetics,and type of inhibition of CYP450 enzyme by AT-Ⅱwere studied by using the probe-based determination method of human liver microsome system with the related data of IC50 and Ki as evaluation indexes.The metabolism of AT-Ⅱwas affected by CYP1A2,CYP2C9 and CYP3A4 inhibitors,and the highest inhibition rates were41.35%,41.97%and 82.45%,respectively.The IC50 values of AT-Ⅱto five subtypes of P450 CYP2C9,CYP1A2,CYP2C19,CYP3A4 and CYP2D6 were 69.7,84.3,92.4,173.8 and 190.1μmol/L,respectively.The Ki values of AT-Ⅱto five subtypes of P450 CYP2C9,CYP1A2,CYP2C19,CYP3A4 and CYP2D6 were 190.6,179.1,>200,72.2 and 66.8,respectively.Among these enzymes,AT-Ⅱexhibited non-competitive inhibition on CYP1A2,showed competitive inhibition on CYP2C9 and CYP3A4,and displayed mixed AT-Ⅱinhibition on CYP2C19 and CYP2D6.CYP1A2,CYP2C9 and CYP3A4 were involved in the AT-Ⅱmetabolism,and AT-Ⅱexhibited different inhibitory mechanisms and strengths for the five subtypes of CYP450.

Investigating the Effect of Metabolic Phenotypes on Health Events in Alcoholic and Nonalcoholic Fatty Liver Disease

Background and Aims:Metabolic dysfunction and obe-sity commonly coexist with both alcoholic and nonalcoholic fatty liver disease(AFLD and NAFLD).The association of AFLD and NAFLD with incident diseases in individuals with different metabolic phenotypes are unclear.Methods:UK Biobank study participants were screened for the presence of fatty liver at baseline.Body mass index and metabolic dysfunction were used to define metabolic phenotypes.Cox regression model was performed to examine the associations of AFLD and NAFLD with incident significant liver diseases(SLDs),cardiovascular diseases(CVDs),chronic kidney dis-eases(CKDs),and cancers,respectively.Results:A total of 43,974 AFLD and 103,248 NAFLD cases were identified.Both AFLD and NAFLD were associated with an increased risk of diseases of interest.The effects were amplified by obesity and metabolic abnormalities and modified by metabolic phe-notypes.Compared to individuals free of fatty liver and with phenotype of metabolically healthy-normal weight,AFLD[hazard ratio(HR 3.27;95%CI:1.95-5.47)]and NAFLD(HR 2.25;95%CI:1.28-3.94)cases with phenotype of met-abolically obese-normal weight had the greatest risk of SLDs.For CVDs,CKDs,and cancer,the greatest risks were detected in AFLD and NAFLD cases with phenotype of metabolically obese-overweight/obesity.In this subpopulation,AFLD and NAFLD conferred a 2.75-fold(95%CI:2.32-3.25)and 4.02-fold 95%CI:(3.64-4.43)increased risk of CVDs,4.37-fold 95%CI:(3.38-5.64)and 6.55-fold 95%CI:(5.73-7.48)increased risk of CKDs,and 1.19-fold 95%CI:(1.08-1.27)and 1.21-fold 95%CI:(1.14-1.28)increased risk of cancers,respectively.Conclusions:Metabolic phenotypes modified the association of AFLD and NAFLD with intrahepatic and ex-trahepatic diseases.

Metabolic phenotyping of mouse mutants in the German Mouse Clinic

The German Mouse Clinic was established as a phenotyping center to provide the scientific community with systematic standardized phenotyping of mouse models from various genetic backgrounds.We found metabolic phenotypes in nine out of 20 mutant lines screened in a primary screen.Based on these findings,the mutants were analyzed in secondary and tertiary screens.Mice of a sample mutant line,isolated from the ENU-screen at the National Research Center for Environment and Health in Munich,were found to have lower body weight,consume less food,but have higher ratios of metabolized energy per unit body weight compared with their wild-type littermates.Basal metabolic rate and heat production were simultaneously increased by 16–18%,whereas body fat content was reduced by 11–16%.The combination of various parameters of energy consumption,expenditure and energy storage illustrate the metabolic demands of the sample mutant mouse line and demonstrate the utility of the powerful phenotyping tool used at the German Mouse Clinic.

Advances in Liquid Chromatography-Mass Spectrometry-Based Lipidomics: A Look Ahead

Lipidomics is a subfield of metabolic phenotyping that focuses on high-throughput profiling and quantification of lipids.Essential roles of lipidomics in translational and clinical research have emerged,especially over the past decade.Most lipidomic pipelines have been developed using mass spectrometry(MS)-based methods.Because of the complexity of the data,generally,computational demands are much higher in untargeted lipidomic studies.In the current paper,we primarily discussed the recent advances in untargeted liquid chromatography-mass spectrometry-based lipidomics,covering various facets from analytical strategies to functional interpretations.The current practice of tandem MS-based lipid annotation in untargeted lipidomics studies was demonstrated.Notably,we highlighted the essential characteristics of machine learning models,together with a data partitioning strategy,to facilitate appropriate modeling and validation in metabolic phenotyping studies.Critical aspects of data sharing were briefly mentioned.Finally,certain recommendations were suggested toward more standardized and sustainable lipidomics analysis strategies as independent platforms,and as members of the omics family.

Liquiritin ameliorates metabolic and endocrine alterations in a mouse model of polycystic ovary syndrome

Objective::Altered bile acid transformation induces low-grade chronic inflammation and may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). Liquiritincan regulate bile acid metabolism and anti-inflammatory properties;however, limited information is available regarding its therapeutic potential in PCOS.Methods::Female C57BL/6 mice were randomly assigned into four groups ( n = 6 mice/group): the control, letrozole or dehydroepiandrosterone-induced PCOS groups, PCOS + 20 mg/kg liquiritin group, and control + liquiritin groups. After 21 days of treatment, the mice were euthanized, and the associated metabolism indications were investigated. Ovarian histological examinations were performed, and serum hormone concentration was measured. The expression of key genes involved in steroid hormone synthesis, ovarian follicle development, and ovulation was assessed. Results::Liquiritin reduced fasting blood glucose levels and increased insulin sensitivity compared to the PCOS group. Liquiritin also significantly decreased serum levels of total testosterone ( P < 0.001) and dehydroepiandrosterone sulfate ( P < 0.05) in the PCOS group. Histomorphological inspection of ovaries from the liquiritin group revealed fewer cystic dilated follicles than in the PCOS group. Moreover, liquiritinsignificantly ( P < 0.01) decreased Cyp17a1, Cyp19a1, Fshr, Hsd3b2, Runx2, and Ccn2 mRNA expression compared to letrozole-induced PCOS. Conclusion::Liquiritin may be safe and helpful in ameliorating PCOS-associated hyperandrogenemia and hyperglycemia. However, clinical trials investigating different liquiritin dosages are needed to confirm these findings.