Lipid Accumulation In Liver Research Articles

Short-term exposure to low doses of aflatoxin B1 aggravates nonalcoholic steatohepatitis by TLR4-mediated necroptosis.

Aflatoxin B1 (AFB1), a worldwide mycotoxin found in food and foodstuffs, is a potent hepatotoxin in humans and animals. Non-alcoholic fatty liver disease (NAFLD), a widespread disease, could progress from simple steatosis to non-alcoholic steatohepatitis (NASH), hepatic cirrhosis, and even hepatocellular carcinoma (HCC). To date, little is known concerning the relationship between AFB1 and the progression of NAFLD. The effects of low doses of AFB1 on the development of NASH and their mechanism were investigated in vivo and in vitro. The results in vivo showed that AFB1 at 20 and 40 μg/kg.bw aggravated CDAHFD-induced NASH in mice as demonstrated by increasing the serum and liver lipid accumulation, liver inflammation and injury. The results in vitro showed that AFB1 at 1.0 μM aggravated FFA-induced lipid accumulation, inflammation and cell damage in HepG2 cells. In addition, RNA-seq indicated that necroptosis, Toll like receptor signaling and TNF-α signaling showed a significant change in KEGG pathway enrichment in AFB1 at 40 μg/kg.bw. AFB1 significantly upregulated the mRNA and protein levels of TLR4, RIPK3, p-RIPK3, MLKL and p-MLKL, and increased TUNEL positive cells. Also, immunofluorescence results showed that TUNEL, TLR4, TNF-α had co-localized with RIPK3, respectively. Necroptosis inhibitor (GSK-872) attenuated the aggravating effects of AFB1 on NASH. Knockout of TLR4 inhibited necroptosis and rescued the aggravating effects of AFB1 on NASH. These data indicate that low dose of AFB1 aggravated NASH via TLR4-mediated necroptosis. This suggests that low dose of AFB1 is potentially harmful to animals and humans, as they exacerbate NASH.

Attenuation of high-fat diet-induced weight gain by apolipoprotein A4.

Apolipoprotein A4 (APOA4) is synthesized by the small intestine in response to dietary lipids. Chronic exposure to a high-fat diet (HFD) desensitizes lipid-induced APOA4 production and attenuates brown adipose tissue (BAT) thermogenesis. We hypothesized that exogenous APOA4 could increase BAT thermogenesis and energy expenditure in HFD-fed mice, resulting in decreased obesity and improved glucose tolerance. BAT and inguinal white adipose tissue (IWAT) thermogenesis, body composition, energy intake and expenditure, and locomotor activity were measured using an infrared camera, immunoblots, quantitative magnetic resonance imaging, and a comprehensive lab animal monitoring system. An intraperitoneal glucose tolerance test and hepatic lipid accumulation and steatosis were assayed. Mice receiving continuous infusion of APOA4 for the last 4 weeks of 10 weeks of HFD feeding gained no additional body weight and had reduced fat mass but enhanced BAT and IWAT thermogenesis and energy expenditure, despite unaltered food intake and locomotor activity. Additionally, APOA4 infusion elevated fatty acid β oxidation; decreased lipogenesis, lipid accumulation, and steatosis in liver; and improved glucose tolerance. Maintenance of plasma APOA4 via exogenous APOA4 protein parallels elevation of BAT and IWAT thermogenesis, hepatic fatty acid β oxidation, and overall energy expenditure, with subsequent prevention of additional weight gain in HFD-fed obese mice.

Comparative Transcriptome Analysis Reveals the Impact of a High-Fat Diet on Hepatic Metabolic Function in Tilapia (Oreochromis niloticus)

Hepatic steatosis is prevalent among cultured fish, yet the molecular mechanisms remain incompletely understood. This study aimed to assess changes in hepatic metabolic function in tilapia and to explore the underlying molecular mechanisms through transcriptomic analyses. Tilapia were allocated into two groups: a normal control (Ctr)-fed group and a high-fat diet (HFD)-fed group. Serum biochemical analyses revealed that HFD feeding led to liver damage and lipid accumulation, characterized by elevated levels of glutamic-pyruvic transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), triglycerides (TGs), and total cholesterol (TC). Transcriptome analysis showed that 538 genes were significantly downregulated, and 460 genes were significantly upregulated in the HFD-fed fish. Gene Ontology (GO) enrichment analysis showed that these differentially expressed genes (DEGs) were apparently involved in the lipid metabolic process and monocarboxylic acid metabolic process. Meanwhile, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated significant alterations in pathways of steroid biosynthesis, porphyrin metabolism, terpenoid backbone biosynthesis, and retinol metabolism after HFD feeding. Additionally, results from Gene Set Enrichment Analysis (GSEA) revealed that gene expression patterns in pathways including oxidative phosphorylation, protein export, protein processing in the endoplasmic reticulum, and ribosome biogenesis were positively enriched in the HFD-fed tilapia. These findings provide novel insights into the mechanisms underlying HFD-induced hepatic dysfunction in fish, contributing to the optimization of feeding strategies in aquaculture.

Guanidine-Derived Polymeric Nanoinhibitors Target the Lysosomal V-ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation.

Current research efforts in polymer and nanotechnology applications are primarily focused on cargo delivery to enhance the therapeutic index, with limited attention being paid to self-molecularly targeted nanoparticles, which may also exhibit significant therapeutic potential. Long-term and anomalous lipid accumulation in the liver is a highly relevant factor contributing to liver diseases. However, the development of the reliable medications and their pharmacological mechanisms remain insufficient. Herein, a polyguanide nanoinhibitors (PGNI) depot is constructed by copolymerizing biguanide derivatives in different proportions onto prepolymers. The nanoinhibitors for their ability to ameliorate lipid accumulation in vitro and in vivo is screened, and subsequently demonstrated that covalently polymeric guanidine chains exhibit superior efficacy in ameliorating hepatic lipid accumulation via heterogeneous mechanisms compared to small-molecule guanidine. It is found that PGNIs stabilize guanidine metabolism in the liver, preferably for biosafety. More importantly, PGNI is ingested and localized in hepatocyte lysosomes and is locked to interact with vesicular adenosine triphosphatase (V-ATPase) on lysosomes, leading to the inhibition of V-ATPase and lysosomal acidification, thereby activating the AMPK pathway, reducing fatty acid synthesis, and enhancing lipolysis and fatty acid oxidation. These results imply that polymer-formed nanoparticles can serve as targeted inhibitors, offering a novel approach for therapeutic applications.

Docosahexaenoic acid alleviated liver lipid deposition and health damage induced by cholesterol accumulation in hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂)

Cholesterol accumulation can be a critical pathological marker and, while, the cholesterol-lowering potential of docosahexaenoic acid (DHA) has been documented extensively in mammals, its effects in fish are unclear. The present study investigated the adverse effects of cholesterol accumulation on liver health, and evaluated DHA as a potential cholesterol-lowering agent to mitigate liver damage induced by high cholesterol (HC) intake in hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂). Grouper were fed either a control diet or an HC (1.6 %) diet supplemented with varying levels of DHA (0, 0.5, 1, 2 %) for eight weeks. The HC diet significantly increased condition factor (CF), mesenteric fat index (MFI), and lipid, cholesterol and triglyceride accumulation in liver. Supplementing the HC diet with 0.5 % DHA significantly reduced CF, MFI and liver lipid contents. Moreover, HC intake increased aspartate transaminase (AST) and alanine transaminase (ALT) activities in serum, and malondialdehyde (MDA) content and the expression of gene related to inflammatory responses and apoptosis in liver. In addition, HC intake significantly reduced mitochondrial biogenesis and total antioxidant capacity in liver. However, supplementing the HC diet with 0.5 % DHA significantly decreased liver cholesterol accumulation by inhibiting cholesterol synthesis and promoting cholesterol efflux, and significantly reduced liver triglyceride content by inhibiting the expression of genes associated with lipogenesis and lipid droplet formation. Furthermore, supplementation of the HC diet with 0.5 % DHA significantly reduced the activities of ALT and AST in serum, and MDA content and the expression of genes associated with inflammation, apoptosis and antioxidation in liver, and enhanced liver mitochondrial biogenesis. Overall, the results indicated that DHA supplementation mitigated liver cholesterol accumulation by inhibiting cholesterol synthesis and promoting cholesterol efflux, and enhanced mitochondrial function, boosted antioxidant capacity, and reduced inflammation in liver of grouper fed the HC diet, ultimately alleviating liver damage caused by cholesterol accumulation. The present study elucidated the detrimental effects of cholesterol accumulation on liver health in aquatic animals and proposed DHA as a potential intervention for mitigating health issues associated with cholesterol overload.

Artemisia capillaris Thunb. Water Extract Alleviates Metabolic Dysfunction-associated Steatotic Liver Disease Disease by Inhibiting miR-34a-5p to Activate Sirt1-mediated Hepatic Lipid Metabolism

Artemisia capillaris Thunb. (ACT) is a plant in the Asteraceae family. Its traditional effects are to clear away dampness and heat, promote gallbladder and reduce jaundice. Traditional Chinese medicine believes that MASLD is a damp-heat syndrome. The group's previous study showed that Artemisia capillaris Thunb. Water Extract (ACTE) has an improved effect on MASLD. In order to further understand its mechanism of action, this study established a mouse MASLD model and a HepG2 cell lipid droplet model, combined small RNA sequencing and miRNA transfection experiments, to explore the mechanism of ACTE to improve MASLD by modulating miRNA-targeted mRNA. Non-targeted metabolomics method was used to detect and analyze ACTE. This study screened miR-34a-5p and confirmed its target mRNA-Sirtuin 1 (Sirt1). MASLD induced high expression of miR-34a-5p and low expression of Sirt1, and ACE reversed these changes. When overexpressing miR-34a-5p or knocking down Sirt1, the effect of ACE in reducing PO (palmitic acid and oleic acid complex)-induced lipid accumulation in HepG2 cells was attenuated. ACTE reduces the expression of FASN, SCD1, ACC, and SREBP-1c, promotes the expression of CPT-1 and HSL, thereby reducing lipid accumulation. ACTE activates Sirt1 by inhibiting the expression of miR-34a-5p, thereby reducing liver lipid accumulation and improving HFD-induced MASLD. These findings highlight the potential of ACTE in reducing weight, controlling obesity, and improving lipid metabolism disorders.

Pea Albumin Alleviates Oleic Acid-Induced Lipid Accumulation in LO2 Cells Through Modulating Lipid Metabolism and Fatty Acid Oxidation Pathways.

Excessive lipid accumulation in the liver can cause NAFLD, leading to chronic liver injury. To relieve liver lipid accumulation by dietary proteins, this study used oleic acid (OA) induction to establish a stable in vitro LO2 cell lipid accumulation model. This model was used to explore the mechanism by which pea albumin (PA) regulates lipid levels in LO2 cells. PA has been shown to ameliorate OA-induced lipid accumulation in LO2 cells by reducing the aggregation of intracellular lipid droplets and lowering cell TG and TC levels. In addition, it can alleviate OA-induced LO2 cell damage and oxidative stress, reduce cellular ALT and AST secretion, lower cellular MDA levels, and increase GSH-Px viability. Regulation of lipid metabolism in LO2 cells involves inhibiting the cellular lipid synthesis pathway and activating the expression of proteins related to the triglyceride catabolic and fatty acid oxidation pathways. PA contributes to regulating lipid accumulation in LO2 cells. This study provides new insights into alleviating liver fat accumulation and a theoretical basis for exploring the mechanism of protein regulation of liver cell lipid metabolism.

Blumea balsamifera and Sargassum aquifolium extracts reduce fatty liver damage through lipid metabolism signalling pathways

Non-alcoholic fatty liver disease (NAFLD) is a condition marked by excessive fat accumulation in the liver and poses a significant health challenge. The leaves of Blumea balsamifera and Sargassum aquifolium have been reported to have anti-atherogenic effects. This study aims to determine the effectiveness of B. balsamifera extract (BBLE) and S. aquifolium extract (SAE) in preventing and treating liver fat accumulation in Wistar rats induced by a high-cholesterol diet through the expression of the AMP-activated protein kinase (AMPK)/ Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor γ (PPARγ) pathway, and the leptin receptor. The experimental design of this study is laboratory-based, involving, 20 Wistar rats were fed a high-cholesterol diet over a period of 21 days. The rats were divided into four groups for the evaluation of BBLE and SAE effect: negative control (P0): induced with a high-cholesterol diet + distilled water, positive control (P1): induced with a high-cholesterol diet + simvastatin, P2: induced with a high-cholesterol diet + 4 mg/kg/bw BBLE, and P3: induced with a high-cholesterol diet + 4 mg/kg/bw BBLE and 4 mg/kg/bw SAE. The treatment duration extended over three months. Immunohistochemical analyses were performed on liver tissues to measure AMPK, SIRT1, PPARγ, and leptin receptor expression. The results indicated that leptin expression was lower in the BBLE+SAE group compared to the simvastatin group, and differences were significant between the BBLE and BBLE+SAE groups. No significant differences were noted in AMPK, SIRT1, and PPARγ expression between the simvastatin and BBLE+SAE groups (p≥0.05). In conclusion, BBLE and SAE effectively reduce liver lipid accumulation and enhance fat metabolism in hypercholesterolemic rats.

Dipeptidyl peptidase IV inhibitors reduce hepatic fibrosis and lipid accumulation in rat intestinal failure-associated liver disease models.

This study aimed to investigate the effectiveness of dipeptidyl peptidase IV inhibitors (DPP4-I) against liver damage, especially fibrosis and lipid accumulation, in a rat intestinal failure-associated liver disease (IFALD) model. SD rats were divided into two groups: the Control (n = 7; normal saline + IFALD model) and DPP4-I (n = 7; DPP4-I + IFALD model; short bowel syndrome (SBS) + total parenteral nutrition) groups. All rats were euthanized 21days postoperatively to obtain tissue samples. Liver fibrosis was evaluated by Sirius Red and α-SMA staining. Liver damage was assessed using the steatosis, activity, and fibrosis score. Inflammation cytokines were examined by ELISA. The survival rate was comparatively different, being 87.5% in the DPP4-I group and 70.0% in the Control group. Two rats of the Control group showed progressive liver fibrosis in the periportal area with fibrous streaks. Further, the mean area percentage of α-SMA immune-positive cells was significantly lower in the DPP4-I group than in the Control group. TGF-β levels were significantly lower in the DPP4-I group than in the Control group. DPP4-I administration reduced liver fibrosis in IFALD, possibly by inhibiting DPP4-I-induced adipogenesis and suppressing TGF-β. These results may contribute to elucidating the mechanism of IFALD.

Functional study of amine oxidase copper-containing 1 (AOC1) in lipid metabolism

Amine oxidase copper-containing 1 (AOC1) is a key member of copper amine oxidase family, which is responsible for deamination oxidation of histamine and putrescine. In recent years, AOC1 has been reported to be associated with various cancers, with its expression levels significantly elevated in certain cancer cells, suggesting its potential role in cancer progression. However, its function in lipid metabolism still remains unclear. Through genetic analysis, we have discovered a potential relationship between AOC1 and lipid metabolism. To further investigate, we generated Aoc1 -/- mice and characterized their metabolic phenotypes on both chow diet and high-fat diet (HFD) feeding conditions. On HFD feeding conditions, Aoc1 -/- mice exhibited significantly higher fat mass and impaired glucose sensitivity, and lipid accumulation in white adipose tissue and liver was also increased. This study uncovers the potential role of AOC1 in lipid metabolism and its implications in metabolic disorders such as obesity and type 2 diabetes, providing new targets and research directions for treating metabolic diseases.

Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy

Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liver dysfunctions such as increased susceptibility to metabolic dysfunction-associated fatty liver disease (MAFLD) and heightened sensitivity to certain drugs. Here, we generated a liver-specific DM1 mouse model that reproduces molecular and pathological features of the disease, including susceptibility to MAFLD and reduced capacity to metabolize specific analgesics and muscle relaxants. Expression of CUG-expanded (CUG)exp repeat RNA within hepatocytes sequestered muscleblind-like proteins and triggered widespread gene expression and RNA processing defects. Mechanistically, we demonstrate that increased expression and alternative splicing of acetyl-CoA carboxylase 1 drives excessive lipid accumulation in DM1 livers, which is exacerbated by high-fat, high-sugar diets. Together, these findings reveal that (CUG)exp RNA toxicity disrupts normal hepatic functions, predisposing DM1 livers to injury, MAFLD, and drug clearance pathologies that may jeopardize the health of affected individuals and complicate their treatment.

Atractylodes lancea Rhizome Polysaccharide Alleviates MCD Diet-Induced NASH by Inhibiting the p53/mTOR Pathway.

Nonalcoholic steatohepatitis (NASH) is a form of chronic liver disease that is characterized by liver inflammation and steatosis, with possible progression to fibrosis. Currently, no drugs have been approved for the treatment of NASH. In this study, we isolated a polysaccharide from Atractylodes lancea rhizome (AP) and established a methionine- and choline-deficient (MCD) diet -induced NASH mouse model to investigate the preventive effect and potential mechanism of AP on NASH. The results showed that AP effectively reduced liver lipid accumulation and inflammation and reduced autophagy and ferroptosis in hepatocytes, thereby preventing the development of NASH. These findings suggest that AP may be a promising natural candidate for the treatment of NASH.

Elevated Porcupine Disrupts Lipid Metabolism and Promotes Inflammatory Response in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a high incidence globally and is a major cause of cirrhosis and hepatocellular carcinoma, lacking of efficient interventions. Patients with MASLD exhibit exceeded serum levels of palmitic acid (PA). However, the association between PA and MASLD remains obscure. Gene expression omnibus dataset analysis, western blotting, mRNA-sequencing, RT-qPCR, a click chemistry-immunoprecipitation-immunofluorescence system, ELISA, lipid extraction and UHPLC-MS/MS analysis, CyTOF mass cytometry, gene knockdown via lentivirus-mediated shRNA, and high-fat methionine and choline-deficient diet-fed WT and db/db mice models were used to reveal the expression and functions of Porcupine in MASLD development both invitro and invivo. Our findings show that PA, as a crucial substrate for protein palmitoylation, induced the expression of palmitoyltransferase Porcupine in a time-dependent manner. This induction was closely associated with dysregulated lipid metabolism and stimulated inflammatory response observed invitro. Porcupine protein levels were significantly increased in liver tissues from both MASLD mice models, which was predominantly localised in lipid droplet-rich hepatocytes. Pharmacological inhibition of Porcupine by Wnt974 markedly ameliorated the aberrant lipid accumulation and inflammatory response in mouse livers. Furthermore, increased Porcupine positively correlated with CD36 at protein levels, and its inhibition or knockdown decreased CD36 protein levels via mechanisms irrelevant to transcriptional regulation, but primarily dependent on protein palmitoylation. The current study reveals that PA-induced Porcupine disrupts lipid metabolism and promotes inflammatory response during MASLD development, which can be ameliorated by the Porcupine inhibitor Wnt974. Therefore, Porcupine may be a potential pharmacological target for the treatment of MASLD.

Antidiabetic Effect of Bifidobacterium animalis TISTR 2591 in a Rat Model of Type 2 Diabetes.

This study investigated the beneficial effects of probiotic Bifidobacterium animalis TISTR 2591 on the regulation of blood glucose and its possible mechanisms in a rat model of type 2 diabetes. The type 2 diabetic-Sprague Dawley rats were established by the combination of a high-fat diet and a low dose of streptozotocin. After 4weeks of treatment with 2 × 108CFU/ml of B. animalis TISTR 2591, fasting blood glucose (FBG), oral glucose tolerance, serum insulin, and pancreatic and hepatic histopathology were determined. Liver lipid accumulation, glycogen content, and gluconeogenic protein expression were evaluated. Oxidative stress and inflammatory status were determined. B. animalis TISTR 2591 significantly reduced FBG levels and improved glucose tolerance and serum insulin in the diabetic rats. Structural damage of the pancreas and liver was ameliorated in the B. animalis TISTR 2591-treated diabetic rats. In addition, significant decreases in hepatic fat accumulation, glycogen content, and phosphoenolpyruvate carboxykinase-1 protein expression were found in the diabetic rats treated with B. animalis TISTR 2591. The diabetic rats showed a significant reduction of inflammation following B. animalis TISTR 2591 supplementation, as demonstrated by decreasing hepatic NF-κB protein expression and serum and liver TNF-α levels. The B. animalis TISTR 2591 significantly decreased MDA levels and increased antioxidant SOD and GPx activities in the diabetic rats. In conclusion, B. animalis TISTR 2591 was shown to be effective in controlling glucose homeostasis and improving glucose tolerance in the diabetic rats. These beneficial activities were attributed to reducing oxidative and inflammatory status and modulating hepatic glucose metabolism.

7005 Characterization of Clinical Candidate Miricorilant in Preclinical Models for NASH

Abstract Disclosure: T.J. Moll: None. E.M. Viho: None. M. Gentenaar: None. H. Hunt: Employee; Self; Corcept Therapeutics. O.C. Meijer: Grant Recipient; Self; Corcept Therapeutics. J. Kroon: Research Investigator; Self; Corcept Therapeutics. Background and aim: Miricorilant (CORT118335) is a selective glucocorticoid receptor (GR) modulator that is under clinical development for the treatment of non-alcohol steatohepatitis (NASH). It was previously shown that miricorilant treatment effectively lowers hepatic lipid content in mouse models of NASH. The aim of this study is to further characterize the effects of miricorilant in the mouse liver and in human liver tissue. Methods: In mouse liver tissue, we investigated the agonistic and antagonistic properties of miricorilant on GR activity. Eight-week-old male C57BL/6J mice were fed with a control diet or miricorilant-supplemented diet (resulting in an estimated dose of 60 mg/kg/day) for 6 days and 1.5 mg/kg corticosterone was injected to monitor the effects of miricorilant on GR-responsive gene expression. We next accessed the time-dependency of the lipid-lowering effects of miricorilant in the mouse liver. Mice were fed with a high-fat, high-fructose diet (HFHFD) for 3 weeks before treatment with 60 mg/kg/day miricorilant for one, three or six days by oral gavage, and triglyceride content in the liver was measured at endpoint. In human liver tissue, we investigated the effects of miricorilant on precision-cut liver slices (PCLS) obtained from two independent donors with pre-existing steatosis. PCLS were cultured for a total of 168 hours in the presence of 100 nM hydrocortisone, and with or without an exogenous lipid challenge. PCLS were treated with 200-600 nM miricorilant for 96 hours before triglyceride content was measured. RNA-sequencing was performed on PCLS after 24 hours of 200-400 nM miricorilant exposure. Results: In the mouse liver, miricorilant exhibited a unique combination of agonistic and antagonistic properties on GR-responsive gene expression. Miricorilant effectively lowered HFHFD-induced lipid accumulation in the mouse liver as soon as three days after treatment. In human PCLS, miricorilant treatment lowered triglyceride content in both donors. RNA-sequencing revealed respectively 40 and 128 differentially expressed genes after 200 and 400 nM miricorilant treatment. Pathway analysis revealed very-low-density lipoprotein (VLDL) particle remodeling as a significant enriched pathway, providing a possible explanation for the lowered triglyceride content upon miricorilant treatment. Conclusion: Miricorilant rapidly and effectively lowers hepatic lipid content in the mouse liver and in human PCLS, possibly via modulation of VLDL remodeling. Presentation: 6/2/2024

Sulforaphane Improves Liver Metabolism and Gut Microbiota in Circadian Rhythm Disorder Mice Models Fed With High-Fat Diets.

This study aims to investigate the effect of sulforaphane (SFN) on hepatic metabolism and gut microbiota in a shifted circadian rhythm (CR) mouse model fed with a high-fat diet (HFD). A shifted CR mouse model with HFD is constructed. Biochemical analyses are used to evaluate the effects of SFN on lipid accumulation and liver function. Targeted metabolomics is used for liver metabolites. Results from hematoxylin and eosin staining and Oil Red O staining show that SFN improves liver lipid accumulation and intestinal inflammatory damage in shifted CR treatment with HFD. The concentrations of amino acid metabolites are increased, and the levels of bile acid metabolites are significantly decreased by SFN treatment. Results from 16S rRNA gene sequencing indicate that SFN modulates gut microbiota, particularly by enhancing beneficial bacteria such as Lachnospiraceae, Lactobacillus, Alistipes, Akkermansia, and Eubacteriaum coprostanoligenes. Correlation analysis confirms a close relationship between intestinal microbiota and hepatic metabolites. SFN significantly regulates CR protein expression in the hypothalamus and liver tissues. SFN alleviates hepatic metabolic disorder and gut microbiota dysbiosis induced by CR disruption under a high-fat diet in a mouse model, indicating the potential of SFN in regulating CR disruption.

Effects of high α-linolenic acid transgenic rapeseed oil diet on growth performance, fat deposition, flesh quality, antioxidant capacity, and immunity of juvenile largemouth bass (Micropterus salmoides).

Omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) increases in aquatic products contributes to improving meat quality, thereby positively impacting human health. Different from marine fish which primarily obtain n-3 LC-PUFAs directly from zooplankton and algae, freshwater fish mainly utilize dietary linolenic acid (ALA) as a substrate to synthesize n-3 LC-PUFAs. Our team has successfully created a transgenic rapeseed oil (TRO) with high ALA content. Therefore, we here assessed the impacts of four different diets (LR, low-fat rapeseed oil (RO) diet; HR, high-fat RO diet; LTR, low-fat TRO diet; HTR, high-fat TRO diet) on growth performance, lipid accumulation, fatty acid composition, antioxidant capacity, immunity and serum biochemical indexes of juvenile largemouth bass (Micropterus salmoides), an economically valuable freshwater fish. The results showed no significant difference in survival rate among the four dietary groups. No significant differences in body weight gain and final weight were found between the LR and LTR groups, as well as between HR and HTR groups. No matter if it was a high-fat or low-fat diet, compared with the RO diet, TRO diets significantly increased the content of n-3 LC-PUFA, improved meat quality, effectively alleviated lipid accumulation in livers and muscles of juvenile largemouth bass. In addition, using high-fat diets, TRO diet improved the antioxidant capacity and immune ability of juvenile largemouth bass, thereby promoting the overall health of fish. This study provides novel insights for fish feed formulation optimization from the perspective of genetically modified feed ingredients, and high-quality aquatic products for human consumption.

Schisandra chinensis polysaccharide prevents alcohol-associated liver disease in mice by modulating the gut microbiota-tryptophan metabolism-AHR pathway axis

Polysaccharides are one of the main active components of Schisandra chinensis and have been shown to possess diverse biological activities. In this study, we investigated the preventive effect of Schisandra chinensis polysaccharide (SCP) on alcohol-associated liver disease (ALD) by chronic-plus-binge ethanol feeding and the underlying mechanisms. The results suggest that supplementation with SCP prevents ALD by modulating gut microbiota and tryptophan (Trp) metabolism. SCP significantly enriched intestinal Lactobacillus, especially Lactobacillus reuteri, restored the content of intestinal indole derivatives (TRM, IAA, ILA, IALD) that can activate the aromatic hydrocarbon receptor (AHR), increased the colon AHR pathway activity, repaired intestinal barriers damage, reduced the circulating LPS, and inhibited the liver inflammation, oxidative stress, and lipid accumulation. The in vitro Trp metabolizing capacity was used to selected for a strain of L. reuteri whose in vitro proliferation was similarly promoted by SCP. Importantly, the gavage of the L. reuteri increased intestinal TRM content in mice. In addition, its ALD preventive effects were consistent with SCP and dependent on the colon AHR pathway. Our findings confirm that SCP may prevent ALD by mudulating the gut microbial-Trp metabolism-AHR pathway axis, suggesting that supplementation with the prebiotic SCP is an effective way to prevent ALD.

Non-invasive hepatic steatosis and fibrosis indices predict differentially mortality in the adult Korean population

Since the association of hepatic fibrosis and steatosis non-invasive indices with mortality remain controversial, their association with all-cause, cardiovascular, cancer and liver-related mortality was evaluated in the Korean population. In this registry-based, cohort study, data were retrieved from the Korea National Health and Nutrition Examination Survey and mortality data from the Korean Cause of Death data registry; 40,491 individuals followed-up for 8.6 years (median). Hepatic fibrosis was evaluated with alanine aminotransferase (AST)-to-platelet ratio index (APRI), body mass index-AST-to-alanine aminotransferase (ALT) ratio-diabetes mellitus (BARD) and metabolic dysfunction-associated fibrosis-5 (MAF-5) score, and steatosis was evaluated with liver fat score (LFS) and lipid accumulation product (LAP). Cox regression analysis showed that APRI (<1.0 vs. ≥1.0) was independently associated with all-cause (hazard ratio [HR] 3.84, 95% confidence interval [CI] 2.30-6.43, C-index 0.870), cancer (HR 4.21, 95%CI 1.88-9.45, C-index 0.866) and liver-related (HR 25.36, 95%CI 11.02-58.38, C-index 0.909) mortality. MAF-5 (<1.0 vs. ≥1.0) was independently associated with all-cause mortality (HR 1.50, 95%CI 1.10-2.03, C-index 0.868) and liver-related mortality (HR 8.35, 95%CI 3.58-19.46, C-index 0.911). LFS (<1.257 vs. ≥1.257), was independently associated with all-cause (HR 1.55, 95%CI 1.14-2.12, C-index 0.872) and liver-related (HR 7.00, 95%CI 1.63-29.96, C-index 0.887) mortality. LAP (<38.05 vs. ≥38.05) was independently associated with cardiovascular mortality (HR 2.23, 95%CI 1.40-3.58, C-index 0.898). BARD was not associated with mortality. APRI, MAF-5, LFS were independently associated with all-cause mortality, LAP (cut-off 38.05) with cardiovascular mortality, APRI with cancer mortality, and APRI, MAF-5, LFS with liver-related mortality in the adult Korean population.

Integrated metabolomics and network pharmacology analysis to reveal the protective effect of Complanatoside A on nonalcoholic fatty liver disease.

The rising prevalence and severe consequences of nonalcoholic fatty liver disease (NAFLD) have driven the quest for preventive medications. Complanatoside A (CA) is the marked flavonoid of Astragali complanati semen, a traditional Chinese herb that acts on the liver meridian and is widely used to treat liver problems. CA has been proven to have considerable lipid-lowering and liver-protective effects in vitro. However, the efficacy of CA in preventing NAFLD has yet to be shown in vivo. First, the effectiveness of CA against NAFLD was assessed using a high-fat diet (HFD) mouse model. Second, the CA protective mechanism against NAFLD was investigated using a combined metabolomics and network pharmacology strategy. Differential metabolites were identified by metabolomics-based analyses, and metabolic pathway analysis was accomplished by MetaboAnalyst. Potential therapeutic targets were obtained through network pharmacology. Finally, key targets were identified via compound-target networks and validated by molecular docking and western blotting. CA prevented NAFLD mainly by reducing liver lipid accumulation in HFD mice. Metabolomics identified 22 potential biomarkers for CA treatment of NAFLD, primarily involving glycerophospholipid and arachidonic acid metabolism. Fifty-one potential targets were determined by network pharmacology. Co-analysis revealed that albumin, peroxisome proliferator-activated receptor-alpha, retinoid X receptor alpha, interleukin-6, and tumor necrosis factor alpha were key targets. This experiment revealed that CA has a preventive effect on NAFLD, primarily by regulating the peroxisome proliferator-activated receptor-alpha/retinoid X receptor alpha pathway. Furthermore, it provides evidence supporting the potential use of CA in the long-term prevention of NAFLD.