Liver Metabolomics Research Articles

Mechanism of acteoside in prevention and treatment of gouty arthritis based on liver metabolomics

This study aims to reveal the effect of acteoside on gouty arthritis(GA) in rats based on liver metabolomics. The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to search for the potential biomarkers and metabolic pathways. SD rats were randomly assigned into blank, model, colchicine(0.3 mg·kg~(-1)), and high-, medium-, low-dose(200, 100, and 50 mg·kg~(-1), respectively) acteoside groups(n=7). The rats were administrated once a day for 7 continuous days. Monosodium urate(MSU) was used to induce GA model in rats during administration. The degree of joint swelling and pathological changes of synovial tissue in rats were observed, and the levels of interleukin(IL)-1β, IL-18 and tumor necrosis factor(TNF)-α in the synovial tissue of rats were measured. UPLC-Q-TOF-MS was employed to collect rat liver data, and Progenesis QI and EZ info were used for data analysis. Human Metabolomics Database(HMDB) and Kyoto Encyclopedia of Genes and Genomes(KEGG) were employed to predict the potential biomarkers and metabolic pathways. The results showed that acteoside alleviated joint swelling, reduced synovial tissue damage, and lowered the levels of inflammatory cytokines in GA rats. A total of 19 common biomarkers were identified, 17 of which can be regulated by acteoside. Seven metabolic pathways were enriched, such as glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism, among which glycerophospholipid metabolism was strongly disturbed. The metabolomics analysis suggested that acteoside may down-regulate the expression of inflammatory cytokines and alleviate the symptoms of GA rats by regulating glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism. The findings provide a reference for future research and development of acteoside.

Potential treatment of glutathione in bullfrogs with abnormal hepatic lipid metabolism revealed by hepatic lipid metabolism and serum metabolomics analysis.

With the continuous growth of bullfrog supply, it has become an important aquaculture species. Due to the lack of actionable industry standards and regulation, the misuse of anti-disease drugs and abnormal liver lipid metabolism in bullfrogs have become a major obstacle to the development of bullfrog aquaculture industry. Glutathione is a natural tripeptide that can be synthesized intracellularly, and its physiological functions mainly include the treatment of liver diseases, antioxidant, detoxification, anti-tumor, enhancement of immunity, and delaying aging. In this study, the therapeutic effect of glutathione on bullfrogs with abnormal liver lipid metabolism was revealed from hepatic lipid metabolism and serum metabolomics analysis. The survival rate, liver histomorphology, serum antioxidant enzyme activity, liver lipase activity and serum metabolomics, liver metabolomics were studied and analyzed by feeding the bullfrogs with abnormal lipid metabolism with glutathione for 20 days in the NC, FI and GSH groups. The results of the study showed that glutathione was able to repair the liver and improve the survival rate of bullfrogs with abnormal lipid metabolism; the activity of serum SOD enzymes was significantly increased; the activities of ACP and AKP were significantly decreased; the activities of HDL-C and T-CHO were significantly increased; and the activities of LDL-C, TBA, and TG were significantly decreased in the liver; the contents of metabolites, such as PC, PS, and PE were significantly up-regulated, and the levels of up-regulated Autophagy - other, Necroptosis and ErbB signaling pathway, and down-regulated Sphingolipid metabolism, D-Amino acid metabolism metabolic pathway, to some extent The metabolic pathways of Sphingolipid metabolism and D-Amino acid metabolism were down-regulated to alleviate the disorders of glycerophospholipid and amino acid metabolism to a certain extent, thus alleviating the abnormalities of liver lipid metabolism. The results showed that glutathione could effectively treat the liver lipid metabolism disorder of bullfrogs, promote the growth and development of bullfrogs, repair the liver function, reduce the inflammation, and promote the healthy and green development of bullfrog industry.

Lanifibranor Reduces Inflammation and Improves Dyslipidemia in Lysosomal Acid Lipase-Deficient Mice

Background and AimsRecent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy (ERT), however, liver histolopathology improved in some but not all patients. We hypothesized that the pan-PPAR agonist lanifibranor may have beneficial effects on liver inflammation in LAL knockout (Lal-/-) mice based on its promising results in alleviating liver inflammation in patients with metabolic dysfunction-associated steatohepatitis. MethodsFemale Lal-/- mice were daily gavaged with lanifibranor or vehicle for 21 days. The effects of the treatment were assessed by measuring body and organ weights, plasma lipids and lipoproteins, as well as hematological parameters, followed by liver proteomics and metabolomics. ResultsLanifibranor treatment slightly altered organ weights without affecting the total body weight of Lal-/- mice. We observed major changes in the proteome, with multiple proteins related to lipid metabolism, peroxisomal, and mitochondrial activities being upregulated and inflammation-related proteins being downregulated in the livers of treated mice. Hepatic lipid levels and histology remained unaltered, whereas plasma triacylglycerol and total cholesterol levels were decreased and the lipoprotein profile of lanifibranor-treated Lal-/- mice improved. ConclusionsLanifibranor treatment positively affected liver inflammation and dyslipidemia in Lal-/- mice. These findings suggest the necessity of a further combined study of lanifibranor with ERT in Lal-/- mice to improve the phenotype. Moreover, there is a compelling rationale for conducting clinical trials to assess the efficacy of lanifibranor as a potential treatment option for LAL-D in humans.

Tyrosol regulates hepatic lipid metabolism in high-fat diet-induced NAFLD mice.

This study aimed to elucidate the effect of tyrosol (TYR) on the amelioration of nonalcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.025% (w/w) TYR (TYR) for 16 weeks. Following a 16-week intervention, the TYR cohort exhibited diminished final body weight and hepatic lipid accumulation, compared to HFD fed mice. Liver metabolomics analysis revealed that TYR increased the hepatic levels of spermidine, taurine, linoleic acid, malic acid and eicosapentaenoic acid (EPA), indicating the beneficial effect of TYR on lipid homeostasis. Using molecular docking analysis and the luciferase assay, we found that TYR acts as a ligand and binds with peroxisome proliferator-activated receptor-α (PPARα), which plays a pivotal role in the modulation of hepatic lipid metabolism, thereby activating the transcription of downstream genes. Our results suggest that TYR alleviates NAFLD in HFD-fed mice probably by the modulation of the PPARα signaling pathway.

Gut microbiota and liver metabolomics reveal the potential mechanism of Lactobacillus rhamnosus GG modulating the liver toxicity caused by polystyrene microplastics in mice.

Microplastics (MPs) are known to cause liver toxicity as they can spread through the food chain. Most researches on their toxicity have focused on individual organs, neglecting the crucial "gut-liver axis"-a bidirectional communication pathway between the gut and liver. Probiotics have shown promise in modulating the effects of environmental pollutants. In this study, we exposed mice to Lactobacillus rhamnosus GG (LGG, 100 mg/kg b.w./d) and/or polystyrene microplastics (PS-MPs, 5 mg/kg b.w./d) for 28 d via gavage to investigate how probiotics influence live toxicity through the gut-liver axis. Our results demonstrated that PS-MPs induced liver inflammation (increased IL-6 and TNF-α) and disrupted lipid metabolism. However, when combined with LGG, these effects were alleviated. LGG also improved colon health, rectifying ciliary defects and abnormal mucus secretion caused by PS-MPs. Furthermore, LGG improved gut microbiota dysbiosis induced by PS-MPs. Metabolomics and gene expression analysis (Cyp7a1 and Cyp7b1) indicated that LGG modulated bile acid metabolism. In summary, LGG appears to protect the liver by maintaining gut homeostasis, enhancing gut barrier integrity, and reducing the liver inflammation. These findings confirm the potential of LGG to modulate liver toxicity caused by PS-MPs through the gut-liver axis, offering insights into probiotics' application for environmental pollutant detoxification.

Liver metabolomics reveals potential mechanism of Jieduan-Niwan formula against acute-on-chronic liver failure (ACLF) by improving mitochondrial damage and TCA cycle

BackgroundAcute-on-chronic liver failure (ACLF) is a refractory disease with high mortality, which is characterized by a pathophysiological process of inflammation-related dysfunction of energy metabolism. Jieduan-Niwan formula (JDNWF) is a eutherapeutic Chinese medicine formula for ACLF. However, the intrinsic mechanism of its anti-ACLF effect still need to be studied systematically.PurposeThis study aimed to investigate the mechanism of JDNWF against ACLF based on altered substance metabolic profile in ACLF the expression levels of related molecules.Materials and methodsThe chemical characteristics of JDNWF were characterized using ultra performance liquid chromatography (UPLC) coupled with triple quadrupole mass spectrometry. Wistar rats subjected to a long-term CCL4 stimulation followed by a combination of an acute attack with LPS/D-GalN were used to establish the ACLF model. Liver metabolites were analyzed by LC–MS/MS and multivariate analysis. Liver function, coagulation function, histopathology, mitochondrial metabolic enzyme activity and mitochondrial damage markers were evaluated. The protein expression of mitochondrial quality control (MQC) was investigated by western blot.ResultsLiver function, coagulation function, inflammation, oxidative stress and mitochondrial enzyme activity were significantly improved by JDNWF. 108 metabolites are considered as biomarkers of JDNWF in treating ACLF, which were closely related to TCA cycle. It was further suggested that JDNWF alleviated mitochondrial damage and MQC may be potential mechanism of JDNWF improving mitochondrial function.ConclusionsMetabolomics revealed that TCA cycle was impaired in ACLF rats, and JDNWF had a regulatory effect on it. The potential mechanism may be improving the mitochondrial function through MQC pathway, thus restoring energy metabolism.

Role of gut microbiota on regulation potential of Dendrobium officinale Kimura & Migo in metabolic syndrome: In-vitro fermentation screening and in-vivo verification in db/db mice

Ethnopharmacological relevanceDendrobium officinale Kimura & Migo (DEN) is a traditional medicine in China since Han dynasty. Decoction of its stem is often used in the treatment of Type-II diabetes (T2D), which is a typical metabolic disease accompanied with the impaired metabolic function of blood glucose and lipid. Aim of the studyOur study aimed to investigate the role of gut microbiota in differentiating DEN from different sources and its related pathway in the alleviation of metabolic syndromes induced by T2D. Materials and methodsThe aqueous extracts of four commercially available Dendrobium (DEN-1∼4) were prepared and screened through an in-vitro fermentation system. Based on their alterations in monosaccharide composition and short chain fatty acids (SCFA) formation during fermentation with db/db faecal fluid, one DEN extract was selected for further in vivo verification. The selected Dendrobium (DEN-4) was orally administered to db/db mice for 16 days once daily at the dosage of 200 mg/kg followed by evaluating its effect on blood glucose level, liver function and intestinal microenvironment including alterations of intestinal integrity and gut microbiota composition. In addition, liver metabolomics analysis was employed to reveal the related metabolic pathways. ResultsDifferent extent of SCFA formation and utilization of monosaccharides were observed for the extracts of four DEN from different sources with a negative correlation between SCFA level and the ratio of Utilized glucose/Utilized mannose observed in the in-vitro fermentation system with db/db faecal fluid. DEN-4 with the highest SCFA formation during the in-vitro fermentation was selected and exhibited significantly hypoglycaemic effect in db/db mice with the alleviation of hepatic steatosis and impaired lipid homeostasis. Further mechanistic studies revealed that orally administered DEN-4 could improve the intestinal integrity of db/db mice via elevating their tight junction protein (ZO-1 and Occludin) expression in the colon and improve the diversity of gut microbiota with enhanced formation of SCFA. Moreover, metabolomics and KEGG pathway analysis of liver tissues suggested that the alleviated metabolic syndrome in db/db mice by DEN-4 might possibly be achieved through activation of PPAR pathway. ConclusionOur current study not only revealed the potential of gut microbiota in differentiating DEN from different sources, but also demonstrated that DEN exhibited its beneficial effect on the T2D induced metabolic syndrome possibly through enhancement of intestinal integrity and activation of PPAR pathway via gut-liver axis in db/db mice.

Effects of pomelo sponge fermented by Monascus ruber on cholesterol metabolism and intestinal microbiota in high-fat diet mice

The purpose of this study is to produce Monascus ruber fermented pomelo sponge products (MFPS) utilizing low-cost pomelo sponge as a solid-state fermentation substrate, and to investigate the effects of MFPS on cholesterol metabolism and gut microbiota in mice. The study of oral MFPS treatment in high-fat diet mice uncovered that a high dosage of MFPS effectively inhibited the increase of body weight, reduced the accumulation of liver and epididymal fat and improved blood cholesterol metabolism in mice. Interestingly, MFPS consumption enhanced the liver's antioxidant capacity, cleared free radicals. Furthermore, HE staining demonstrated that MFPS effectively repaired liver damage. UPLC-QTOF/MS analysis of liver metabolomics revealed that MFPS intervention exerts a substantial regulatory impact on metabolic pathways encompassing alanine, aspartate and glutamate metabolism, biosynthesis of unsaturated fatty acids, steroid hormone biosynthesis, tryptophan metabolism, glycerophospholipid metabolism, fatty acid degradation, folate biosynthesis, etc. High-throughput sequencing of 16S rRNA unveiled that MFPS mitigated the intestinal microbiota imbalance triggered by a high-fat diet, increasing the abundance of probiotics in the intestine, including Lactobacillus and Bifidobacterium. Therefore, these findings demonstrate that MFPS can improve abnormal cholesterol metabolism and balance intestinal flora, offering valuable insights for developing natural and effective cholesterol-lowering products.

Assessing the safety of lipid-modifying medications among Chinese adolescents: a drug-target Mendelian randomization study

BackgroundWith increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics.MethodsA drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong’s “Children of 1997” birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the “Children of 1997” birth cohort and coronary artery disease from Biobank Japan.ResultsGenetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], − 1.06 [− 1.52 to − 0.60]; PCSK9: − 0.93 [− 1.56 to − 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid − 0.79 [− 1.25 to − 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed.ConclusionsStatins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics.

Coping with extremes: Alternations in diet, gut microbiota, and hepatic metabolic functions in a highland passerine

In wild animals, diet and gut microbiota interactions are critical moderators of metabolic functions and are highly contingent on habitat conditions. Challenged by the extreme conditions of high-altitude environments, the strategies implemented by highland animals to adjust their diet and gut microbial composition and modulate their metabolic substrates remain largely unexplored. By employing a typical human commensal species, the Eurasian tree sparrow (Passer montanus, ETS), as a model species, we studied the differences in diet, digestive tract morphology and enzyme activity, gut microbiota, and metabolic energy profiling between highland (the Qinghai-Tibet Plateau, QTP; 3230 m) and lowland (Shijiazhuang, Hebei; 80 m) populations. Our results showed that highland ETSs had enlarged digestive organs and longer small intestinal villi, while no differences in key digestive enzyme activities were observed between the two populations. The 18S rRNA sequencing results revealed that the dietary composition of highland ETSs were more animal-based and less plant-based than those of the lowland ones. Furthermore, 16S rRNA sequencing results suggested that the intestinal microbial communities were structurally segregated between populations. PICRUSt metagenome predictions further indicated that the expression patterns of microbial genes involved in material and energy metabolism, immune system and infection, and xenobiotic biodegradation were strikingly different between the two populations. Analysis of liver metabolomics revealed significant metabolic differences between highland and lowland ETSs in terms of substrate utilization, as well as distinct sex-specific alterations in glycerophospholipids. Furthermore, the interplay between diet, liver metabolism, and gut microbiota suggests a dietary shift resulting in corresponding changes in gut microbiota and metabolic functions. Our findings indicate that highland ETSs have evolved to optimize digestion and absorption, rely on more protein-rich foods, and possess gut microbiota tailored to their dietary composition, likely adaptive physiological and ecological strategies adopted to cope with extreme highland environments.

Omics techniques reveal the toxicity mechanisms of three antiepileptic drugs to juvenile zebrafish (Danio rerio) brain and liver

Epilepsy, a neurological disorder, is characterized by seizures that are an appearance of excessive brain activity and is symptomatically treated with antiepileptic drugs (AEDs). Oxcarbazepine (OCBZ), lamotrigine (LTG), and carbamazepine (CBZ) are widely used AEDs in clinics and are very often detected in aquatic environments. However, neither the sub-lethal effects nor the specific mechanisms of these AEDs’ action on the fish are well understood. In this study, juvenile zebrafish were exposed to a sub-lethal concentration (100 μg/L) of OCBZ, LTG, and CBZ for 28 d, after which indicators of oxidative stress (i.e. superoxide dismutase (SOD) activity, catalase (CAT) activity, and malondialdehyde (MDA) level) and neurotoxicity (i.e. acetylcholinesterase (AChE) activity, γ-aminobutyric acid (GABA) level, and glutamic acid (Glu) level) were measured. Brain SOD activity was significantly increased by three AEDs, while brain CAT activity was significantly inhibited by LTG and CBZ. Liver SOD activity was significantly enhanced by CBZ, and liver CAT activity was significantly induced by OCBZ and LTG. Liver MDA level was significantly increased by three AEDs. Brain AChE activity was significantly increased by LTG and CBZ, and brain GABA level was significantly enhanced by three AEDs. However, there were no significant alterations in the levels of MDA and Glu in zebrafish brain. To ascertain mechanisms of AEDs-induced toxicity, brain transcriptomics and liver metabolomics were conducted in zebrafish. The brain transcriptomics results showed that lots of differentially expressed genes (DEGs) were enriched in the sensory system, the immune system, the digestive system, the metabolic processes, and others in three AEDs treated groups. The metabolomics data indicated dysregulation of glycerophospholipid signaling and lipid homeostasis in zebrafish liver after three AEDs exposure. The overall results of this study improve understanding of the sub-lethal effects and potential molecular mechanisms of action of AEDs in fish.

Liver Metabolomics and Inflammatory Profiles in Mouse Model of Fentanyl Overdose Treated with Beta-Lactams.

Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several preclinical studies have demonstrated the efficacy of beta-lactams in modulating the expression of glutamate transporter-1 (GLT-1) in different body organs, including the liver. The upregulation of GLT-1 by beta-lactams is associated with the attenuation of hyperglutamatergic state, which is a characteristic feature of opioid use disorders. A novel experimental beta-lactam compound with no antimicrobial properties, MC-100093, has been developed to attenuate dysregulation of glutamate transport, in part by normalizing GLT-1 expression. A previous study showed that MC-100093 modulated hepatic GLT-1 expression with subsequent attenuation of alcohol-increased fat droplet content in the liver. In this study, we investigated the effects of fentanyl overdose on liver metabolites, and determined the effects of MC-100093 and ceftriaxone in the liver of a fentanyl overdose mouse model. Liver samples from control, fentanyl overdose, and fentanyl overdose ceftriaxone- or MC-100093-treated mice were analyzed for metabolomics using gas chromatography-mass spectrometry. Heatmap analysis revealed that both MC-100093 and ceftriaxone attenuated the effects of fentanyl overdose on several metabolites, and MC-100093 showed superior effects. Statistical analysis showed that MC-100093 reversed the effects of fentanyl overdose in some metabolites. Moreover, enrichment analysis revealed that the altered metabolites were strongly linked to the glucose-alanine cycle, the Warburg effect, gluconeogenesis, glutamate metabolism, lactose degradation, and ketone body metabolism. The changes in liver metabolites induced by fentanyl overdose were associated with liver inflammation, an effect attenuated with ceftriaxone pre-treatments. Ceftriaxone normalized fentanyl-overdose-induced changes in liver interleukin-6 and cytochrome CYP3A11 (mouse homolog of human CYP3A4) expression. Our data indicate that fentanyl overdose impaired liver metabolites, and MC-100093 restored certain metabolites.

Artemisinin counteracts Edwardsiella tarda-induced liver inflammation and metabolic changes in juvenile fat greenling Hexagrammos otakii

Emerging evidence suggests that artemisinin (ART) can modulate pathogen-induced immune responses and metabolic dysregulation. However, whether this modulation is associated with metabolic pathways related to oxidative stress and inflammation remains unclear. The aim of this study was to investigate the antioxidant and anti-inflammatory effects on the ART-fed juvenile fat greenling Hexagrammos otakii and the associated metabolic pathways in response to ART administration using an integrated biochemical and metabolomic approach. Biochemical analysis and histological examination showed that ART significantly increased body weight gain and improved tissue structure. ART effectively attenuated reactive oxygen species (ROS), malondialdehyde (MDA) and inflammatory responses (NFκB, TNF-α, IL-6, and MCP-1) in the Edwardsiella tarda-induced H. otakii model. Liver metabolomics analysis revealed that twenty-nine metabolites were up-regulated and twenty-one metabolites were down-regulated after ART administration compared to those in pathogen-induced fish. Pathway analysis indicated that ART alleviated the E. tarda-induced inflammation and oxidative stress through two major pathways, namely lipid metabolism and amino acid metabolism. Taken together, ART showed great potential as a natural feed additive against pathogen-induced oxidative stress and inflammation.

Metabolic and Hepatic Effects of Empagliflozin on Nonalcoholic Fatty Liver Mice.

Among chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) is one of the commonest. Although empagliflozin has several therapeutic uses in treating cardiovascular and renal disorders, its impacts and mechanisms on NAFLD are poorly understood. This research aimed to examine the metabolic regulatory mechanism through which empagliflozin protects against NAFLD. Equal grouping of twenty-seven male C57BL/6J mice into those fed a normal diet (NCD), those fed a high-fat diet (HFD), and those fed an HFD with empagliflozin (Empa) was approached. HE, oil red O staining, and Masson staining were utilized for evaluating the pathological damage to the liver and the mice's liver and body weights. Lipids, blood glucose, and inflammation index were compared across the three groups. Liquid chromatography/mass spectrometry (LC-MS) has been employed for identifying liver metabolomics. The findings suggested that empagliflozin mitigated the inflammatory and oxidative stress response associated with the buildup of lipids caused by HFD. Differentially expressed metabolites (DEMs) were identified by metabonomics analysis as present in both the HFD/NCD and Empa/HFD groups. These DEMs were primarily found in lipids and organic acids like lysophosphatidylcholine (lysoPC), lecithin (PC), triglyceride (TG), palmitic acid, and L-isoleucine. Among the enriched pathways that were shown to be important were those involved in the metabolism of histidine, arachidonic acid, the control of lipolysis in adipocytes, and insulin resistance. There was a strong correlation between inflammation and oxidative stress in most of the metabolites. The inflammation and oxidative stress unbalance were ameliorated by empagliflozin. NAFLD mice model showed considerable improvement in metabolic abnormalities and liver protection after treatment with empagliflozin. The process may include the overexpression of L-isoleucine and the downregulation of lysoPC, PC, TG, and palmitic acid to reduce liver harm caused by lipotoxicity.

Comparison of the Effect of Phospholipid Extracts from Salmon and Silver Carp Heads on High-Fat-Diet-Induced Metabolic Syndrome in C57BL/6J Mice.

Metabolic syndrome (MetS) is a global health problem, and EPA/DHA-enriched phospholipids (EPA/DHA-PLs) have been found to have positive effects on MetS improvement. Currently, research on EPA/DHA-PL mainly focuses on special and rare seafood, such as phospholipids derived from krill, sea cucumber, squid, and fish roe. However, it has been recently demonstrated that abundant EPA/DHA-PL can also be found in bulk fish and its by-products. Nonetheless, there is still limited research on the biological activities of EPA/DHA-PL derived from these sources. The aim of this study was to investigate the effect of phospholipid extracts from the heads of salmon and silver carp (S-PLE and SC-PLE) on the high-fat-diet-induced MetS in C57/BL mice. After an 8-week intervention, both SC-PLE and S-PLE had a significant ameliorating effect on MetS. Moreover, SC-PLE was more effective than S-PLE in reducing liver inflammation and fasting glucose. Both of the PL extracts were able to regulate the expression of key genes in lipid synthesis, fatty acid β-oxidation, and insulin signaling pathways. Compared with S-PLE, dietary SC-PLE had a greater influence on liver metabolomics. Pathway enrichment analysis showed that the differential metabolites of SC-PLE were mainly involved in arachidonic acid metabolism and glutathione metabolism. The results indicated that the different metabolic regulation methods of S-PLE and SC-PLE could be related to their variant molecular composition in EPA/DHA-PL.

Pregnane X receptor activation remodels glucose metabolism to promote NAFLD development in obese mice

ObjectiveBoth obesity and exposure to chemicals may induce non-alcoholic fatty liver disease (NAFLD). Pregnane X Receptor (PXR) is a central target of metabolism disrupting chemicals and disturbs hepatic glucose and lipid metabolism. We hypothesized that the metabolic consequences of PXR activation may be modified by existing obesity and associated metabolic dysfunction. MethodsWildtype and PXR knockout male mice were fed high-fat diet to induce obesity and metabolic dysfunction. PXR was activated with pregnenolone-16α-carbonitrile. Glucose metabolism, hepatosteatosis, insulin signaling, glucose uptake, liver glycogen, plasma and liver metabolomics, and liver, white adipose tissue, and muscle transcriptomics were investigated. ResultsPXR activation aggravated obesity-induced liver steatosis by promoting lipogenesis and inhibiting fatty acid disposal. Accordingly, hepatic insulin sensitivity was impaired and circulating alanine aminotransferase level increased. Lipid synthesis was facilitated by increased liver glucose uptake and utilization of glycogen reserves resulting in dissociation of hepatosteatosis and hepatic insulin resistance from the systemic glucose tolerance and insulin sensitivity. Furthermore, glucagon-induced hepatic glucose production was impaired. PXR deficiency did not protect from the metabolic manifestations of obesity, but the liver transcriptomics and metabolomics profiling suggest diminished activation of inflammation and less prominent changes in the overall metabolite profile. ConclusionsObesity and PXR activation by chemical exposure have a synergistic effect on NAFLD development. To support liver fat accumulation the PXR activation reorganizes glucose metabolism that seemingly improves systemic glucose metabolism. This implies that obese individuals, already predisposed to metabolic diseases, may be more susceptible to harmful metabolic effects of PXR-activating drugs and environmental chemicals.

Electroacupuncture treatment ameliorates metabolic disorders in obese ZDF rats by regulating liver energy metabolism and gut microbiota.

Metabolic disorders represent a major therapeutic challenge to public health worldwide due to their dramatically increasing prevalence. Acupuncture is widely used as adjuvant therapy for multiple metabolic diseases. However, detailed biological interpretation of the acupuncture stimulations is still limited. The gut and the liver are intrinsically connected and related to metabolic function. Microbial metabolites might affect the gut-liver axis through multiple mechanisms. Liver metabolomics and 16S rRNA sequencing were used to explore the specific mechanism of electroacupuncture in treating ZDF rats in this study. Electroacupuncture effectively improved glycolipid metabolism disorders of the ZDF rats. Histopathology confirmed that electroacupuncture improved diffuse hepatic steatosis and hepatocyte vacuolation, and promoted glycogen accumulation in the liver. The treatment significantly improved microbial diversity and richness and upregulated beneficial bacteria that maintain intestinal epithelial homeostasis and decreased bacteria with detrimental metabolic features on host metabolism. Liver metabolomics showed that the main effects of electroacupuncture include reducing the carbon flow and intermediate products in the TCA cycle, regulating the metabolism of various amino acids, and inhibiting hepatic glucose output and de novo lipogenesis. The gut-liver axis correlation analysis showed a strong correlation between the liver metabolites and the gut microbiota, especially allantoin and Adlercreutzia. Electroacupuncture treatment can improve abnormal energy metabolism by reducing oxidative stress, ectopic fat deposition, and altering metabolic fluxes. Our results will help us to further understand the specific mechanism of electroacupuncture in the treatment of metabolic diseases.

Metabolomics analysis of the potential mechanism of Yi-Guan-Jian decoction to reverse bone loss in glucocorticoid-induced osteoporosis

BackgroundGlucocorticoid-induced osteoporosis (GIOP) is a disease in which long-term use of glucocorticoid causes bone loss, deterioration of bone microstructure and fracture. Currently, clinical drugs targeting this disease have certain side effects. There is still a need to find effective drugs with fewer side effects. The theory of traditional Chinese medicine suggests that YGJ has therapeutic effect on GIOP, but it has not been explained. Therefore, this study aims to explore the protective effect of YGJ on GIOP mouse models and elucidate the underlying mechanism through LC–MS-based metabolomics analysis.MethodsThe general condition of 8 week age male C57BL/6J mice was recorded after 8 weeks of treatment with dexamethasone (DEX) and YGJ. Bone-related parameters and bone morphology were determined by Micro-CT. HE staining was used to observe the pathological changes of bone tissue. Serum levels of bone metabolism markers were detected by ELISA. Liver metabolomics analysis was conducted to search for the significant markers of anti-GIOP of YGJ and the metabolic pathway affecting it.ResultsAfter treatment, YGJ significantly reversed the weight loss caused by DEX; increase the number of bone trabecular in ROI region, significantly improve the bone-related parameters of GIOP mice, and increase the levels of alkaline phosphatase and osteocalcin. In the study of metabolic mechanism, YGJ reversed 24 potential markers in GIOP mice. These included cortisol, 3-hydroxybutyric acid, taurine, esculin and uric acid, which are closely associated with osteoporosis. Topological analysis results showed that YGJ had the most significant effect on taurine and hypotaurine metabolism, with − log10 (P) > 2.0 and Impact > 0.4.ConclusionsYi-Guan-Jian decoction can increase bone density and improve bone microstructure by regulating the levels of alkaline phosphatase and osteocalcin and reverse bone loss in GIOP mouse model. The underlying metabolic mechanism may be related to taurine and hypotaurine metabolic pathway.

Short-term exposure to enrofloxacin causes hepatic metabolism disorder associated with intestinal flora dysbiosis in adult marine medaka (Oryzias melastigma)

Enrofloxacin (ENR) is a widely used fluoroquinolone antibiotic that is frequently detected in the environment. Our study assessed the impact of short-term ENR exposure on the intestinal and liver health of marine medaka (Oryzias melastigma) using gut metagenomic shotgun sequencing and liver metabolomics. We found that ENR exposure resulted in imbalances of Vibrio and Flavobacteria and enrichments of multiple antibiotic resistance genes. Additionally, we found a potential link between the host's response to ENR exposure and the intestinal microbiota disorder. Liver metabolites, including phosphatidylcholine, lysophosphatidylcholine, taurocholic acid, and cholic acid, in addition to several metabolic pathways in the liver that are closely linked to the imbalance of intestinal flora were severely maladjusted. These findings suggest that ENR exposure has the potential to negatively affect the gut–liver axis as the primary toxicological mechanism. Our findings provide evidence regarding the negative physiological impacts of antibiotics on marine fish.

Intestinal microbiomics and hepatic metabolomics insights into the potential mechanisms of probiotic Bifidobacterium pseudolongum CCFM1253 preventing acute liver injury in mice.

Bifidobacterium pseudolongum is widely exists in mammal gut and its abundance is associated with human and animal health. The present study aimed to investigate the potential mechanisms of B. pseudolongum CCFM1253 on protecting against lipopolysaccharide (LPS)-induced acute liver injury (ALI) by metagenomic analysis and liver metabolomic profiles. Bifidobacterium pseudolongum CCFM1253 preintervention remarkably attenuated the influence of LPS on serum alanine transaminase and aspartate amino transferase activities. B. pseudolongum CCFM1253 preintervention remarkably attenuated the inflammation responses (tumor necrosis factor-α, interleukin-1β, and interleukin-6) and elevated antioxidative enzymes activities [total antioxidant capacity, superoxide dismutase, catalase, and glutathione peroxidase] in ALI mice by intervening in the Nf-kβ and Nrf2 pathways, respectively. Bifidobacterium pseudolongum CCFM1253 treatment elevated the proportion of Alistipes and Bifidobacterium, and decreased the proportion of uncultured Bacteroidales bacterium, Muribaculum, Parasutterella and Ruminococcaceae UCG-010 in ALI mice, which were strongly correlated with the inhibition of inflammation responses and oxidative stress. Untargeted liver metabolomics exhibited that the hepatoprotective efficacy of B. pseudolongum CCFM1253 might be achieved by altering liver metabolites-related riboflavin metabolism, phenylalanine metabolism, alanine, citrate cycle (tricarboxylic acid cycle), and so on. Furthermore, riboflavin exposure could control the contents of malondialdehyde, superoxide dismutase, and catalase in hydrogen peroxide-treated HepG2 cells. Bifidobacterium pseudolongum CCFM1253 can effectively alleviate inflammatory response and oxidative stress, and regulate the intestinal microbiota composition and liver metabolism, and elevate the liver riboflavin content in LPS-treated mice. Therefore, B. pseudolongum CCFM1253 could serves as a potential probiotic to ameliorate the host health. © 2023 Society of Chemical Industry.