Saikosaponin D improves nonalcoholic fatty liver disease via gut microbiota-bile acid metabolism pathway

Non-alcoholic fatty liver disease(NAFLD)is the main cause of chronic liver disease worldwide.Bupleurum is widely used in the treatment of non-alcoholic fatty liver,and saikosaponin D(SSD)is one of the main active components of Bupleurum.The purpose of this study was to investigate the efficacy of SSD in the treatment of NAFLD and to explore the mechanism of SSD in the improvement of NAFLD based on“gut-liver axis”.Our results showed that SSD dose-dependently alleviated high fat diet-induced weight gain in mice,improved insulin sensitivity,and also reduced liver lipid accumulation and injury-related biomarkers aspartate aminotransferase(AST)and alanine aminotransferase(ALT).Further exploration found that SSD inhibited the mRNA expression levels of farnesoid X receptor(Fxr),small heterodimer partner(Shp),recombinant fibroblast growth factor 15(Fgf15)and apical sodium dependent bile acid transporter(Asbt)in the intestine,suggesting that SSD improved liver lipid metabolism by inhibiting intestinal FXR signaling.SSD can significantly reduce the gut microbiota associated with bile salt hydrolase(BSH)expression,such as Clostridium.Decreased BSH expression reduced the ratio of unconjugated to conjugated bile acids,thereby inhibiting the intestinal FXR.These data demonstrated that SSD ameliorated NAFLD potentially through the gut microbiota-bile acidintestinal FXR pathway and suggested that SSD is a promising therapeutic agent for the treatment of NAFLD.

Transcriptomic Landscape Analysis Reveals a Persistent DNA Damage Response in Metabolic Dysfunction-associated Steatohepatitis Post-dietary Intervention

Background and Aims:Metabolic dysfunction-associated steatotic liver disease(MASLD)and its more advanced form,metabolic dysfunction-associated steatohepatitis,have emerged as the most prevalent liver diseases worldwide.Currently,lifestyle modification is the foremost guidelinerecommended management strategy for MASLD.However,it remains unclear which detrimental signals persist in MASLD even after disease remission.Thus,we aimed to examine the persistent changes in liver transcriptomic profiles following this reversal.Methods:Male C57BL/6J mice were divided into three groups:Western diet(WD)feeding,chow diet(CD)feeding,or diet reversal from WD to CD.After 16 weeks of feeding,RNA sequencing was performed on the mice’s livers to identify persistent alterations characteristic of MASLD.Additionally,RNA sequencing databases containing high-fat diet-fed P53-knockout mice and human MASLD samples were utilized.Results:WD-induced MASLD triggered persistent activation of the DNA damage response(DDR)and its primary transcription factor,P53,long after the resolution of the hepatic phenotype through dietary reversal.Elevated levels of P53 might promote apoptosis,thereby exacerbating metabolic dysfunction-associated steatohepatitis,as they strongly correlated with hepatocyte ballooning,an indicator of apoptosis activation.Moreover,P53 knockout in mice led to downregulated expression of apoptosis signaling in the liver.Mechanistically,P53 may regulate apoptosis by transcriptionally activating the expression of apoptosis-enhancing nuclease(AEN).Consistently,P53,AEN,and the apoptosis process all exhibited persistently elevated expression and showed a strong inter-correlation in the liver following dietary reversal.Conclusions:The liver demonstrated upregulation of DDR signaling and the P53-AEN-apoptosis axis both during and after exposure to WD.Our findings provide new insights into the mechanisms of MASLD relapse,highlighting DDR signaling as a promising target to prevent MASLD recurrence.

An integrative profiling of metabolome and transcriptome in the plasma and skeletal muscle following an exercise intervention in diet-induced obese mice

Exercise intervention at the early stage of type 2 diabetes mellitus(T2DM)can aid in the maintenance of blood glucose homeostasis and prevent the development of macrovascular and microvascular complications.However,the exercise-regulated pathways that prevent the development of T2DM remain largely unclear.In this study,two forms of exercise intervention,treadmill training and voluntary wheel running,were conducted for high-fat diet(HFD)-induced obese mice.We observed that both forms of exercise intervention alleviated HFD-induced insulin resistance and glucose intolerance.Skeletal muscle is recognized as the primary site for postprandial glucose uptake and for responsive alteration beyond exercise training.Metabolomic profiling of the plasma and skeletal muscle in Chow,HFD,and HFD-exercise groups revealed robust alterations in metabolic pathways by exercise intervention in both cases.Overlapping analysis identified nine metabolites,including beta-alanine,leucine,valine,and tryptophan,which were reversed by exercise treatment in both the plasma and skeletal muscle.Transcriptomic analysis of gene expression profiles in the skeletal muscle revealed several key pathways involved in the beneficial effects of exercise on metabolic homeostasis.In addition,integrative transcriptomic and metabolomic analyses uncovered strong correlations between the concentrations of bioactive metabolites and the expression levels of genes involved in energy metabolism,insulin sensitivity,and immune response in the skeletal muscle.This work established two models of exercise intervention in obese mice and provided mechanistic insights into the beneficial effects of exercise intervention on systemic energy homeostasis.

Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored.Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2 E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2 E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha(PPARa) target genes,including fibroblast growth factor(FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2 e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2 E1 and to serve as PPARa agonists, thus explaining how CYP2 E1 deficiency causes hepatic PPARa activation through increasing cellular levels of endogenous PPARa agonists. Translationally, a CYP2 E1 inhibitor was found to activate the PPARa-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Pparanull mice. The present results establish a metabolic crosstalk between PPARa and CYP2 E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2 E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.