Rifaximin alleviates metabolic dysfunction-associated fatty liver disease via CNTF-mediated ERK-SP1-IL4-depedent manner
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ABSTRACT:
ORGANISM(S): Rattus Norvegicus
SUBMITTER: 
Shiyao Chen
PROVIDER: PXD068238 | iProX | Wed Sep 10 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MALFD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Methods: Liver tissue from 21 participants was collected at time of bariatric surgery and analyzed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n=3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. Results: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells (KC) and monocyte-derived macrophages (MdM). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocytes/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis we demonstrate recruitment of MdMs precedes KC loss and liver damage and that MdMs may serve a role in lipid uptake during MAFLD. Conclusions: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans and this occurs prior to changes in KC number. MdMs appear to have a role in lipid uptake during early stages of MALFD.
2023-10-01 | GSE235079 | GEO
Project description:Steatosis Drives monocyte-derived Macrophage Accumulation in Human Metabolic Dysfunction-Associated Fatty Liver Disease
| PRJNA984298 | ENA
Project description:BackgroundNeuregulin (NRG) family is involved in energy metabolism, among which NRG1 is a neuregulin proved to play a protective role in MAFLD cells. But the presice echanism has not been fully illustrated. This study aimed to investigate the role of NRG1 via the ERK/SIRT1 signaling in the pathogenesis of MAFLD.MethodsC57BL/6 mice were fed with high-fat diet for 8 weeks, and then injected with NRG1 (0.3 mg/kg/d) and PD98059 (0.3 mg/kg/d) via tail vein for 5 weeks. HepG2 cells induced by oleic acid and palmitic acid were treated with 20ng/mL NRG1 and 10µmol/L PD98059. The changes of histopathological, biochemical indexes, inflammatory factors, lipid metabolism, apoptosis and autophagy parameters were measured.ResultsThe expressions of NRG1 in MAFLD cell and animal models were significantly lower than that in the control group. After the intervention of ERK inhibitor PD98059, the expression of NRG1 decreased significantly in vivo, but no significant change was observed in vitro. Moreover, NRG1 ameliorated hepatic steatosis, enhanced cell viability, reduced cell apoptosis, and attenuated liver injury both in vitro and in vivo. After NRG1 intervention, the expressions of ERBB2, ERBB3, p-ERK1/2, SIRT1 and p-FOXO1 as well as the LC3II/I ratio in MAFLD cells and liver tissues of MAFLD mice were significantly increased, while the expression of SREBP1c was decreased. The aforementioned therapeutic effect of NRG1 was lost after the intervention of PD98059.ConclusionNRG1 might play a protective role in the pathogenesis of MAFLD by activating the downstream ERK1/2 through ErbB2-ErbB3, which promotes the expression of SIRT1 and autophagy markers. This study might indicate a new therapeutic strategy for MAFLD.
| S-EPMC11783944 | biostudies-literature
Project description:Metabolic dysfunction-associated fatty liver disease (MAFLD) is a disease that causes an abnormal accumulation of fat in the liver, triggering inflammation and fibrosis, the mechanism of which is not fully understood and for which there is a lack of specific drug therapy. Far-infrared radiation (FIR) has demonstrated evident therapeutic efficacy across various diseases, and novel nanomaterial graphene patches can emit it through electric heating. This study aimed to investigate the potential protective effects of FIR against MAFLD. Mice were fed with a MCD diet to mimic MAFLD progression, and histopathology analysis, biochemical analysis, RT-qPCR, and Western blotting analysis were performed to assess the effect of FIR on MAFLD in vivo. The effect of FIR treatment on MAFLD in vitro was investigated by biochemical analysis and gene expression profiling of hepatocytes. Mice subjected to the MCD diet and treated with FIR exhibited reduced hepatic lipid deposition, inflammation, fibrosis and liver damage. The therapeutic effect exerted by FIR in mice may be caused by the enhancement of AMPK phosphorylation and inhibition of the TGFβ1-SMAD2/3 pathway. Besides, FIR intervention alleviated MAFLD in hepatocytes in vitro and the results were verified by gene expression profiling. Our results revealed a promising potential of FIR as a novel therapeutic approach for MAFLD.
| S-EPMC11336198 | biostudies-literature
Project description:We examined the potential utility of L-carnitine for alleviating metabolic dysfunction-associated steatohepatitis (MASH) and preventing the development of hepatocellular carcinoma. Short-term L-carnitine administration ameliorated MASH through its anti-inflammatory effects.
2024-04-24 | GSE261938 | GEO
Project description:BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most prevalent metabolic syndromes worldwide. However, no approved pharmacological treatments are available for MAFLD. Chenpi, one kind of dried peel of citrus fruits, has traditionally been utilized as a medicinal herb for liver diseases. Didymin is a newly identified oral bioactive dietary flavonoid glycoside derived from Chenpi. In this study, we investigated the therapeutic potential of Didymin as an anti-MAFLD drug and elucidated its underlying mechanisms.MethodsHigh-fat diet (HFD)-induced MAFLD mice and alpha mouse liver 12 (AML12) cells were utilized to evaluate the effects and mechanisms of Didymin in the treatment of MAFLD. Liver weight, serum biochemical parameters, and liver morphology were examined to demonstrate the therapeutic efficacy of Didymin in MAFLD treatment. RNA-seq analysis was performed to identify potential pathways that could be affected by Didymin. The impact of Didymin on Sirt1 was corroborated through western blot, molecular docking analysis, microscale thermophoresis (MST), and deacetylase activity assay. Then, a Sirt1 inhibitor (EX-527) was utilized to confirm that Didymin alleviates MAFLD via Sirt1. Western blot and additional assays were used to investigate the underlying mechanisms.ResultsOur results suggested that Didymin may possess therapeutic potential against MAFLD in vitro and in vivo. By promoting Sirt1 expression as well as directly binding to and activating Sirt1, Didymin triggers downstream pathways that enhance mitochondrial biogenesis and function while reducing apoptosis and enhancing lipophagy.ConclusionsThese suggest that Didymin could be a promising medication for MAFLD treatment. Furthermore, its therapeutic effects are mediated by Sirt1.
| S-EPMC10731721 | biostudies-literature
Project description:Consumption of beans protects from the development of obesity. We established that dietary bean exerts dose- and sex-dependent effects on the liver transcriptome in the context of lipid metabolism, which prevents the onset of metabolic-associated fatty liver disease.
2023-03-12 | GSE227120 | GEO
Project description:Whether bone marrow modulates systemic metabolism remains unknown. Our recent study suggested that myeloid-derived growth factor (MYDGF) improves insulin resistance. Here, we found that myeloid cell-specific MYDGF deficiency aggravated hepatic inflammation, lipogenesis, and steatosis, and show that myeloid cell-derived MYDGF restoration alleviated hepatic inflammation, lipogenesis, and steatosis. Additionally, recombinant MYDGF attenuated inflammation, lipogenesis, and fat deposition in primary mouse hepatocytes (PMHs). Importantly, inhibitor kappa B kinase beta/nuclear factor-kappa B (IKKβ/NF-κB) signaling is involved in protection of MYDGF on non-alcoholic fatty liver disease (NAFLD). These data revealed that myeloid cell-derived MYDGF alleviates NAFLD and inflammation in a manner involving IKKβ/NF-κB signaling, and serves as a factor involved in the crosstalk between the liver and bone marrow that regulates liver fat metabolism. Bone marrow functions as an endocrine organ and serves as a potential therapeutic target for metabolic disorders.
| S-EPMC10293205 | biostudies-literature
Project description:Hydrogen exhibits therapeutic and preventive effects against various diseases. The present study investigated the potential protective effect and dose‑dependent manner of hydrogen inhalation on high fat and fructose diet (HFFD)‑induced nonalcoholic fatty liver disease (NAFLD) in Sprague‑Dawley rats. Rats were randomly divided into four groups: i) Control group, regular diet/air inhalation; ii) model group, HFFD/air inhalation; iii) low hydrogen group, HFFD/4% hydrogen inhalation; and iv) high hydrogen group, HFFD/67% hydrogen inhalation. After a 10‑week experiment, hydrogen inhalation ameliorated weight gain, abdominal fat index, liver index and body mass index of rats fed with HFFD and lowered the total area under the curve in an oral glucose tolerance test. Hydrogen inhalation also ameliorated the increase in liver lipid content and alanine transaminase and aspartate transaminase activities. Liver histopathologic changes evaluated with hematoxylin and eosin as well as Oil Red O staining revealed lower lipid deposition in hydrogen inhalation groups, consistent with the decrease in the expression of the lipid synthesis gene SREBP‑1c. The majority of the indicators were affected following treatment with hydrogen in a dose‑dependent manner. In conclusion, hydrogen inhalation may play a protective role by influencing the general state, lipid metabolism parameters, liver histology and liver function indicators in the rat model of metabolic syndrome with NAFLD.
| S-EPMC7453621 | biostudies-literature
Project description:Objective Metabolic-associated fatty liver disease (MAFLD) has only recently been proposed; therefore, the characteristics of patients with autoimmune hepatitis (AIH) and MAFLD remain unclear. This study evaluated the effect of MAFLD on AIH patients with AIH. Methods We reevaluated the Japanese Nationwide Survey of AIH in 2018, which involved a survey of patients diagnosed with AIH between 2014 and 2017. We categorized patients with AIH according to the presence or absence of MAFLD and compared the clinical characteristics between the two groups. Results A total of 427 patients (77 men and 350 women) were included in this study. The overall prevalence of MAFLD was 10.5%. Compared to AIH patients without MAFLD, AIH patients with MAFLD had the following characteristics at the time of the AIH diagnosis: (1) a higher body mass index, (2) a higher prevalence of hypertension, (3) mild elevation of hepatobiliary enzymes and total bilirubin, and (4) histologically progressive fibrosis. However, the levels of hepatobiliary enzymes and total bilirubin after treatment were significantly higher in AIH patients with MAFLD than in those without MAFLD. Conclusion AIH patients with MAFLD had characteristics different from those of AIH patients without MAFLD. These findings could help increase our understanding of patients with AIH with MAFLD.
| S-EPMC11867740 | biostudies-literature