RESUMO
Supplementation with fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) effectively reduces acute and chronic alcohol-induced hepatic steatosis. We aimed to find molecular mechanisms underlying the effects of n-3 PUFAs in alcohol-induced hepatic steatosis. Because free fatty acid receptor 4 (FFA4, also known as GPR120) has been found as a receptor for n-3 PUFAs in an ethanol-induced liver steatosis model, we investigated whether n-3 PUFAs protect against liver steatosis via FFA4 using AH7614, an FFA4 antagonist, and Ffa4 knockout (KO) mice. N-3 PUFAs and compound A (CpdA), a selective FFA4 agonist, reduced the ethanol-induced increase in lipid accumulation in hepatocytes, triglyceride content, and serum ALT levels, which were not observed in Ffa4 KO mice. N-3 PUFAs and CpdA also reduced the ethanol-induced increase in lipogenic sterol regulatory element-binding protein-1c expression in an FFA4-dependent manner. In Kupffer cells, treatment with n-3 PUFA and CpdA reversed the ethanol-induced increase in tumor necrosis factor-α, cyclooxygenase-2, and NLR family pyrin domain-containing 3 expression levels in an FFA4-dependent manner. In summary, n-3 PUFAs protect against ethanol-induced hepatic steatosis via the anti-inflammatory actions of FFA4 on Kupffer cells. Our findings suggest FFA4 as a therapeutic target for alcoholic hepatic steatosis.
Assuntos
Etanol , Ácidos Graxos Ômega-3 , Fígado Gorduroso Alcoólico , Células de Kupffer , Receptores Acoplados a Proteínas G , Animais , Masculino , Camundongos , Ácidos Graxos Ômega-3/farmacologia , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/prevenção & controle , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Células de Kupffer/metabolismo , Células de Kupffer/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Protetoras/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismoRESUMO
BACKGROUND/AIMS: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. We previously reported that pemafibrate significantly improves liver function, serum triglyceride (TG) levels and liver stiffness in non-alcoholic fatty liver disease patients, however the influence of alcohol consumption was not considered. Therefore, we explored pemafibrate efficacy in patients with steatotic liver disease (SLD) and alcohol-associated liver disease (ALD). METHODS: We retrospectively evaluated pemafibrate efficacy on liver enzymes and lipids in metabolic dysfunction-associated SLD (MASLD) (nâ =â 93), MASLD plus increased alcohol intake (MetALD; nâ =â 23) and ALD (nâ =â 22) patients who had taken pemafibrate for at least 48 weeks. Liver shear wave velocity (SWV, nâ =â 75) was also evaluated. RESULTS: In MASLD group, ALT, aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and TG values were significantly decreased from baseline to week 24 and week 48 ( P â <â 0.0001). ALT and TG values in MetALD group and ALT and AST values in ALD group were also significantly decreased from baseline to week 24 and week 48. Study participant SWV values decreased from baseline to week 48. We observed no significant difference in changes to ALT, AST, γ-GTP and TG (value at week 24 or week 48 minus value at baseline) among the three groups. CONCLUSION: Pemafibrate improves liver function and liver stiffness thus making it a promising therapeutic agent for SLD, even in patients with excess alcohol consumption (MetALD and ALD groups).
Assuntos
Alanina Transaminase , Consumo de Bebidas Alcoólicas , Aspartato Aminotransferases , Benzoxazóis , Butiratos , Fígado , Triglicerídeos , gama-Glutamiltransferase , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , gama-Glutamiltransferase/sangue , Consumo de Bebidas Alcoólicas/efeitos adversos , Resultado do Tratamento , Butiratos/uso terapêutico , Benzoxazóis/uso terapêutico , Alanina Transaminase/sangue , Triglicerídeos/sangue , Aspartato Aminotransferases/sangue , Idoso , Fígado/efeitos dos fármacos , Fígado/patologia , Técnicas de Imagem por Elasticidade , Adulto , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fatores de Tempo , Biomarcadores/sangue , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso Alcoólico/tratamento farmacológicoRESUMO
OBJECTIVE: To analyze the effect and molecular mechanism of Gehua Jiejiu Dizhi decoction (, GJDD) on alcoholic fatty live disease (AFLD) by using proteomic methods. METHODS: The male C57BL/6J mouse were randomly divided into four groups: control group, model group, GJDD group and resveratrol group. After the AFLD model was successfully prepared by intragastric administration of alcohol once on the basis of the Lieber-DeCarli classical method, the GJDD group and resveratrol group were intragastrically administered with GJDD (4900 mg/kg) and resveratrol (400 mg/kg) respectively, once a day for 9 d. The fat deposition of liver tissue was observed and evaluated by oil red O (ORO) staining. 4DLabel-free quantitative proteome method was used to determine and quantify the protein expression in liver tissue of each experimental group. The differentially expressed proteins were screened according to protein expression differential multiples, and then analyzed by Gene ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Finally, expression validation of the differentially co-expressed proteins from control group, model group and GJDD group were verified by targeted proteomics quantification techniques. RESULTS: In semiquantitative analyses of ORO, all kinds of steatosis (ToS, MaS, and MiS) were evaluated higher in AFLD mice compared to those in GJDD or resveratrol-treated mice. 4DLabel-free proteomics analysis results showed that a total of 4513 proteins were identified, of which 3763 proteins were quantified and 946 differentially expressed proteins were screened. Compared with the control group, 145 proteins were up-regulated and 148 proteins were down-regulated in the liver tissue of model group. In addition, compared with the model group, 92 proteins were up-regulated and 135 proteins were down-regulated in the liver tissue of the GJDD group. 15 differentially co-expressed proteins were found between every two groups (model group vs control group, GJDD group vs model group and GJDD group vs control group), which were involved in many biological processes. Among them, 11 differentially co-expressed key proteins (Aox3, H1-5, Fabp5, Ces3a, Nudt7, Serpinb1a, Fkbp11, Rpl22l1, Keg1, Acss2 and Slco1a1) were further identified by targeted proteomic quantitative technology and their expression patterns were consistent with the results of 4D label-free proteomic analysis. CONCLUSIONS: Our study provided proteomics-based evidence that GJDD alleviated AFLD by modulating liver protein expression, likely through the modulation of lipid metabolism, bile acid metabolism and with exertion of antioxidant stress.
Assuntos
Fígado Gorduroso Alcoólico , Serpinas , Camundongos , Masculino , Animais , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/metabolismo , Antioxidantes/metabolismo , Proteômica/métodos , Resveratrol/metabolismo , Esforço Físico , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Metabolismo dos Lipídeos , Ácidos e Sais Biliares/metabolismo , Lipídeos , Serpinas/metabolismo , Aldeído Oxirredutases/metabolismoRESUMO
BACKGROUND: Fatty liver disease (FLD) poses a significant global health concern worldwide, with its classification into nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) contingent upon the presence or absence of chronic and excessive alcohol consumption. The absence of specific therapeutic interventions tailored to FLD at various stages of the disease renders its treatment exceptionally arduous. Despite the fact that FLD and hyperlipidemia are intimately associated, there is still debate over how lipid-lowering medications affect FLD. Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) is a serine protease predominantly synthesized in the liver, which has a crucial impact on cholesterol homeostasis. Research has confirmed that PCSK9 inhibitors have prominent lipid-lowering properties and substantial clinical effectiveness, thereby justifying the need for additional exploration of their potential role in FLD. PURPOSE: Through a comprehensive literature search, this review is to identify the relationship and related mechanisms between PCSK9, lipid metabolism and FLD. Additionally, it will assess the pharmacological mechanism and applicability of PCSK9 inhibitors (including naturally occurring PCSK9 inhibitors, such as conventional herbal medicines) for the treatment of FLD and serve as a guide for updating the treatment protocol for such conditions. METHODS: A comprehensive literature search was conducted using several electronic databases, including Pubmed, Medline, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the database to 30 Jan 2024. Key words used in the literature search were "fatty liver", "hepatic steatosis", "PCSK9", "traditional Chinese medicine", "herb medicine", "botanical medicine", "clinical trial", "vivo", "vitro", linked with AND/OR. Most of the included studies were within five years. RESULTS: PCSK9 participates in the regulation of circulating lipids via both LDLR dependent and independent pathways, and there is a potential association with de novo lipogenesis. Major clinical studies have demonstrated a positive correlation between circulating PCSK9 levels and the severity of NAFLD, with elevated levels of circulating PCSK9 observed in individuals exposed to chronic alcohol. Numerous studies have demonstrated the potential of PCSK9 inhibitors to ameliorate non-alcoholic steatohepatitis (NASH), potentially completely alleviate liver steatosis, and diminish liver impairment. In animal experiments, PCSK9 inhibitors have exhibited efficacy in alleviating alcoholic induced liver lipid accumulation and hepatitis. Traditional Chinese medicine such as berberine, curcumin, resveratrol, piceatannol, sauchinone, lupin, quercetin, salidroside, ginkgolide, tanshinone, lunasin, Capsella bursa-pastoris, gypenosides, and Morus alba leaves are the main natural PCS9 inhibitors. Excitingly, by inhibiting transcription, reducing secretion, direct targeting and other pathways, traditional Chinese medicine exert inhibitory effects on PCSK9, thereby exerting potential FLD therapeutic effects. CONCLUSION: PCSK9 plays an important role in the development of FLD, and PCSK9 inhibitors have demonstrated beneficial effects on lipid regulation and FLD in both preclinical and clinical studies. In addition, some traditional Chinese medicines have improved the disease progression of FLD by inhibiting PCSK9 and anti-inflammatory and antioxidant effects. Consequently, the inhibition of PCSK9 appears to be a promising therapeutic strategy for FLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Inibidores de PCSK9 , Animais , Humanos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso Alcoólico/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores de PCSK9/uso terapêutico , Pró-Proteína Convertase 9/metabolismoRESUMO
AIMS: Alcoholic liver disease (ALD) can develop into cirrhosis and hepatocellular carcinoma but no specific drugs are available. Fenofibrate is therapeutically effective in ALD, however, the exact mechanism remains unknown. We explored the hub genes of ALD and the role of fenofibrate in ALD. MAIN METHODS: The hub genes of ALD were screened by bioinformatics method, and their functional enrichment, signalling pathways, target genes and their correlation with immune microenvironment and pathogenic genes were analysed. We also analysed the binding affinity of fenofibrate to proteins of hub genes using molecular docking techniques, and the effects on hub gene expression, lipid deposition, oxidative stress and inflammation in the liver of National Institute on Alcohol Abuse and Alcoholism (NIAAA) model mice. The regulatory effects of fenofibrate on MOXD1 and PDZK1P1 were investigated after gene silencing of peroxisome proliferator-activated receptor-α (Ppar-α). KEY FINDINGS: Hub genes identified, including monooxygenase DBH-like 1 (MOXD1), PDZK1-interacting protein 1 (PDZK1IP1) and solute carrier 51 ß (SLC51B), are highly predictive for ALD. Hepatic MOXD1 and PDZK1IP1 expression was elevated in patients with ALD and NIAAA model mice, with no significant difference in SLC51B expression between the groups. Fenofibrate binds tightly to MOXD1 and PDZK1IP1, inhibits their hepatic expression independently of PPAR-α signalling, and ameliorates lipid deposition, oxidative stress and inflammatory responses in NIAAA model mice. SIGNIFICANCE: MOXD1 and PDZK1IP1 are key genes in ALD progression; fenofibrate improves liver damage in NIAAA model mice by downregulating their expression. Our findings provide insight for improving diagnostic and therapeutic strategies for ALD.
Assuntos
Fígado Gorduroso Alcoólico , Fenofibrato , Hipercolesterolemia , Hepatopatias Alcoólicas , Camundongos , Humanos , Animais , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Fígado Gorduroso Alcoólico/tratamento farmacológico , Simulação de Acoplamento Molecular , Fígado/metabolismo , Inflamação/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Hipercolesterolemia/metabolismo , Hepatopatias Alcoólicas/patologia , Lipídeos/farmacologia , Proteínas de Membrana/metabolismoRESUMO
BACKGROUND: Ligustilide (Lig) is the main active ingredient of Umbelliferae Angelicae Sinensis Radix (Chinese Angelica) and Chuanxiong Rhizoma (Sichuan lovase rhizome). Lig possesses various pharmacological properties and could treat obesity by regulating energy metabolism. However, the impact and regulatory mechanism of Lig on alcoholic hepatic steatosis remains unclear. PURPOSE: This study aimed to explore the therapeutic effect of Lig on alcoholic hepatic steatosis and its related pharmacological mechanism. RESULTS: With chronic and binge ethanol feeding, liver tissue damage and lipid accumulation in mice suffering alcoholic hepatic steatosis were significantly improved after Lig treatment. Lig effectively regulated the expression levels of lipid metabolism-related proteins in alcoholic hepatic steatosis. In addition, Lig reduced RXFP1 expression, inhibited the activation of NLRP3 inflammasome, and blocked NET formation. Lig reduced the infiltration of immune cells to the liver and the further prevented the occurrence of alcohol-stimulated inflammatory response in liver. Lig significantly regulated lipid accumulation in alcohol exposed AML12 cells via modulating PPARα and SREBP1. In MPMs, Lig decreased the expression of RXFP1, inhibited the activation of NLRP3 in macrophages stimulated by LPS/ATP, and slowed down the occurrence of inflammatory response. CONCLUSION: Lig sustained lipid metabolism homeostasis in alcoholic hepatic steatosis, through inhibiting the activation of NLRP3 inflammasomes and the formation of NETs, especially targeting RXFP1 in macrophages.
Assuntos
4-Butirolactona/análogos & derivados , Fígado Gorduroso Alcoólico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/metabolismo , Fígado/metabolismo , Etanol/uso terapêutico , Inflamassomos , Lipídeos/uso terapêutico , Camundongos Endogâmicos C57BLRESUMO
In the peel of citrus (Rutaceae) fruit, hesperitin (Hesp), a flavanone glycoside chemical, is found naturally. Hesp has been found to have a wide range of pharmacological actions, including anti-inflammatory, antioxidant, antiviral, and anticancer properties, according to earlier research. However, nothing is known regarding its function in alcoholic liver steatosis and inflammation. In this study, we employed a network pharmacology approach to identify the TLR4 signaling pathway as a primary target of Hesp for the treatment of alcoholic steatohepatitis (ASH). Molecular docking results showed that Hesp bound to the representative target TLR4 and exhibited good affinity. In addition, Hesp inhibits the TLR4 target and consequently the NF-κB signaling pathway, which in turn slows the evolution of alcoholic steatohepatitis, according to further in vitro and in vivo tests. The results of this study preliminarily indicate that Hesp is an ideal drug candidate for the treatment of ASH.
Assuntos
Fígado Gorduroso Alcoólico , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Fígado Gorduroso Alcoólico/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Simulação de Acoplamento Molecular , Transdução de SinaisRESUMO
BACKGROUND: Asperosaponin VI (AVI) is a natural triterpenoid saponin isolated from Dipsacus asper Wall with documented anti-inflammatory and bone protective effects. Our previous work reported that AVI protects the liver of septic mice from acute inflammatory damage. In this paper, we further explored the protective effect and the potential mechanisms of AVI in alcoholic fatty liver disease (AFLD). METHODS: The Lieber-Decarli model was constructed to evaluate the effect of AVI on AFLD in C57BL/6 J mice. Additional in vitro work was performed to investigate HepG2 cells exposed to alcohol, then analyzed the degree of liver injury by detecting the ALT and AST levels both in the liver and serum. H&E staining and Sirius red staining were used to evaluate the histopathology variations in the liver. Further, observe lipid droplets in the cytoplasm by Oil Red O staining. We detected the expression of inflammatory cytokines with qualitative PCR; ROS, MDA, SOD, and GSH-px levels were analyzed to observe oxidative stress. Finally, exploring the activation of AMPK signaling pathway by real-time PCR and Western blotting. RESULTS: Histological examination of liver tissue combined with serum ALT and AST levels showed a significant protective effect of AVI against alcoholic liver injury in AFLD mice. Compared with the model group, AVI evidently improved antioxidant capacity, reduced inflammatory response and lipid accumulation both in vitro and in vivo. For mechanically, it was found that AVI up-regulated phosphorylation level of AMP-activated protein kinase (AMPK) and inhibited the endoplasmic reticulum stress (ER) pathway in AFLD. CONCLUSION: AVI protects mice from alcohol-induced hepatic steatosis and liver injury through activating AMPK signaling and repress ER stress, suggesting that it might be a potential therapeutic agent for AFLD.
Assuntos
Fígado Gorduroso Alcoólico , Saponinas , Camundongos , Animais , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/patologia , Metabolismo dos Lipídeos , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos C57BL , Fígado , Saponinas/metabolismo , Estresse Oxidativo , Estresse do Retículo EndoplasmáticoRESUMO
Alcoholic fatty liver disease (AFLD) is a disease with a high incidence rate among individuals who drink alcohol. Our previous study found that agarwood alcohol extracts (AAEs) have a protective effect against druginduced liver damage via antiinflammatory and antioxidant mechanisms. Therefore, we hypothesized that agarwood may have a protective effect against AFLD. The present study assessed the potential protective effects and the underlying mechanism of action of AAEs for the treatment of an AFL in vivo model. The AFLD mouse model was established by continuous high fat diet and alcohol gavage in C57 mice. After treatment with AAEs, blood was collected, liver and adipose tissues were removed and liver and adipose indexes were analyzed. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) and cholesterol (CHO) in serum were detected. The liver tissue was assessed using pathological sections. Biochemical methods were used to detect the levels of oxidative stress in the supernatant of liver tissue homogenate. The levels of proinflammatory cytokines in the serum were detected by ELISA. The protein expression levels of nuclear erythroid 2related factor 2 (Nrf2) and nuclear factor kappaB (NFκB) in liver tissues were detected using western blotting. AAE treatment decreased the liver and adipose indexes, reduced the levels of AST, ALT, TG and CHO, improved the liver pathological characteristics and enhanced antioxidant and antiinflammatory activities. In addition, AAEs increased the protein expression level of Nrf2 and decreased the protein expression level of NFκB compared with AFL mice. AAEtreated animals exhibited reduced metabolic enzyme and blood lipid levels, demonstrated improved liver function and relieved the pathological damage of AFLD induced by consuming a high fat and alcohol diet. AAEs have potential protective effects in AFLD via antioxidant and antiinflammatory mechanisms.
Assuntos
Fígado Gorduroso Alcoólico , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/metabolismo , Antioxidantes/metabolismo , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Etanol/farmacologia , Colesterol/metabolismo , Triglicerídeos/metabolismo , Obesidade/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/metabolismoRESUMO
Fatty liver is the earliest response to excessive ethanol consumption, which increases the susceptibility of the liver to develop advanced stage of liver disease. Our previous studies have revealed that chronic alcohol administration alters metabolic hormone levels and their functions. Of current interest to our laboratory is glucagon-like peptide 1 (GLP-1), a widely studied hormone known to reduce insulin resistance and hepatic fat accumulation in patients with metabolic-associated fatty liver disease. In this study, we examined the beneficial effects of exendin-4 (a GLP-1 receptor agonist) in an experimental rat model of ALD. Male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol diet. After 4 weeks of this feeding regimen, a subset of rats in each group were intraperitoneally injected every other day with either saline or exendin-4 at a dose of 3 nmol/kg/day (total 13 doses) while still being fed their respective diet. At the end of the treatment, rats were fasted for 6 h and glucose tolerance test was conducted. The following day, the rats were euthanized, and the blood and tissue samples collected for subsequent analysis. We found that exendin-4 treatment had no significant effect on body weight gain among the experimental groups. Exendin-4-treated ethanol rats exhibited improved alcohol-induced alterations in liver/body weight and adipose/body weight ratio, serum ALT, NEFA, insulin, adiponectin and hepatic triglyceride levels. Reduction in indices of hepatic steatosis in exendin-4 treated ethanol-fed rats was attributed to improved insulin signaling and fat metabolism. These results strongly suggest that exendin-4 mitigates alcohol-associated hepatic steatosis by regulating fat metabolism.
Assuntos
Fígado Gorduroso Alcoólico , Hepatopatia Gordurosa não Alcoólica , Ratos , Masculino , Animais , Exenatida/farmacologia , Exenatida/uso terapêutico , Ratos Wistar , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/prevenção & controle , Fígado Gorduroso Alcoólico/metabolismo , Insulina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Etanol/toxicidade , Obesidade/metabolismoRESUMO
Repurposing of the widely available and relatively cheap generic cardiac gly-coside digoxin for non-cardiac indications could have a wide-ranging impact on the global burden of several diseases. Over the past several years, there have been significant advances in the study of digoxin pharmacology and its potential non-cardiac clinical applications, including anti-inflammatory, antineoplastic, metabolic, and antimicrobial use. Digoxin holds promise in the treatment of gastrointestinal disease, including nonalcoholic steatohepatitis and alcohol-associated steatohepatitis as well as in obesity, cancer, and treatment of viral infections, among other conditions. In this review, we provide a summary of the clinical uses of digoxin to date and discuss recent research on its emerging applications.
Assuntos
Fígado Gorduroso Alcoólico , Hepatopatia Gordurosa não Alcoólica , Humanos , Digoxina/uso terapêutico , Digoxina/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado Gorduroso Alcoólico/tratamento farmacológico , Obesidade/tratamento farmacológico , Anti-Inflamatórios/uso terapêuticoRESUMO
Steatosis is regarded as an early response of the liver to excessive alcohol consumption, which ultimately results in alcoholic liver disease (ALD). Hepatocytes are the primary drivers of the pathological process known as hepatic damage and steatosis, which is characterized by significant fat accumulation and an abundance of fat vacuoles. NLRs, a family member of pattern recognition receptors, have recently been found to be crucial in liver disorders. In this study, we examined the possible impact of NLRC5, the largest NLR family member, on alcohol-induced fatty liver development using a gene knock-out mouse model. The mouse liver was severely damaged and developed steatosis as a result of chronic and excessive ethanol use, and this damage was prevented by the lack of NLRC5. Additionally, NLRC5 deletion reversed ethanol's ability to increase the serum concentrations of TG, T-CHO, ALT, and AST. Absence of NLRC5 reduced ethanol-stimulated aberrant expression of the vital regulators of lipid synthesis and metabolism, SREBP-1c, FAS and PPAR-α. Furthermore, loss- and gain-of-function research indicated that NLRC5 might affect the autophagy pathway in alcohol-induced hepatic steatosis progression. The functional role of NLRC5 in ALD is obviously impacted by the autophagy inducer rapamycin as well as the autophagy inhibitor 3-MA. Our research showed that NLRC5 was involved in ethanol-induced injury and steatosis of the liver, and may be considered a suitable therapeutic target for treating ALD.
Assuntos
Fígado Gorduroso Alcoólico , Fígado Gorduroso , Hepatopatias Alcoólicas , Camundongos , Animais , Fígado , Fígado Gorduroso/tratamento farmacológico , Etanol , Hepatócitos , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Hepatopatias Alcoólicas/metabolismo , Autofagia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
Alcoholic liver disease (ALD) is a major chronic liver disease. Chronic alcohol consumption induces dysbiosis, disruption of gut barrier function, oxidative stress, inflammation, and changes in lipid metabolism, thereby leading to ALD. In this study, we investigated whether the commercial Morinda citrifolia extract Nonitri can ameliorate ALD symptoms through the gut-liver axis. We used mice chronically administered EtOH and found a marked increase in serum endotoxin levels and biomarkers of liver pathology. Moreover, the EtOH-treated group showed significantly altered gut microbial composition particularly that of Alistipes, Bacteroides, and Muribaculum and disrupted gut barrier function. However, Nonitri improved serum parameters, restored the microbial proportions, and regulated levels of zonula occludens1, occludin, and claudin1. Furthermore, Nonitri suppressed inflammation by inhibiting endotoxin-triggered toll-like receptor 4-signaling pathway and fat deposition by reducing lipogenesis through activating AMP-activated protein kinase in the liver. Furthermore, Pearson's correlation analysis showed that gut microbiota and ALD-related markers were correlated, and Nonitri regulated these bacteria. Taken together, our results indicate that the hepatoprotective effect of Nonitri reduces endotoxin levels by improving gut health, and inhibits fat deposition by regulating lipid metabolism.
Assuntos
Fígado Gorduroso Alcoólico , Hepatopatias Alcoólicas , Morinda , Camundongos , Animais , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/metabolismo , Disbiose/microbiologia , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/prevenção & controle , Fígado/metabolismo , Etanol/metabolismo , Endotoxinas , Inflamação/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Background: At present, the incidence of alcoholic fatty liver disease (AFLD) is increasing year by year, and numerous studies have confirmed that liver diseases are closely related to intestinal flora. Seabuckthorn and Astragalus membranaceus, as traditional Chinese medicine (TCM) with the homology of medicine and food, have good liver protection, and their polysaccharides can regulate the intestinal flora. Here, we studied the effects of HRP, APS and the combination of the two polysaccharides on the intestinal flora of AFLD mice, which provided scientific basis for the treatment of AFLD with the two polysaccharides. Materials and methods: Thirty Kunming (KM) mice were randomly divided into the control group (Con), the model group (Mod), the HRP treatment group (HRP), the APS treatment group (APS), and HRP+APS treatment group (HRP+APS), with six mice in each group. The AFLD model was constructed by continuous intragastric administration of 42% vol Niulanshan ethanol solution for 28 days, and the mice in each polysaccharide group were given corresponding drugs. The levels of AST, ALT, TC and TG in serum of mice were measured. 16S rRNA amplicon sequencing technique was used to determine the diversity and richness of intestinal flora, and the relative abundance of intestinal flora at phylum level and genus level of the mice in each group. Results: HRP, APS and HRP+APS could reduce the serum levels of AST, ALT, TC and TG in mice. In addition, HRP, APS and HRP + APS restored the diversity, relative abundance and community structure of intestinal mucosa bacteria in AFLD mice to a certain extent. Specifically, HRP, APS and HRP+APS remarkably decreased the ratio of Firmicutes to Bacteroidetes, and ultimately increased the abundance of beneficial bacteria and reduced the abundance of pathogenic bacteria. Conclusion: HRP, APS, and HRP+APS can improve the intestinal microecology of AFLD model mice, alleviate liver injury, and maintain normal intestinal function in different degrees.
Assuntos
Astrágalo , Fígado Gorduroso Alcoólico , Microbioma Gastrointestinal , Hippophae , Animais , Astrágalo/química , Etanol , Fígado Gorduroso Alcoólico/tratamento farmacológico , Camundongos , Polissacarídeos/farmacologia , RNA Ribossômico 16SRESUMO
Objective: The mechanism of action of asiatic acid (AA) on alcoholic steatohepatitis (ASH) was investigated using network pharmacology and experiments. Methods: Through data retrieval, network construction, and enrichment analysis, the potential mechanism of AA in the treatment of alcoholic steatohepatitis was explored. Animal and cell models were established in this study. Animal Model. The mouse model was divided into six groups: normal group; model group; low, medium, and high AA group; and silibinin-positive group. Cell Model. An in vitro inflammatory model of RAW264.7 cells was established by alcohol stimulation. Results: Compared with the model group, the low, medium, and high AA group showed decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), and total cholesterol (T-CHO). The inflammatory factor tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) in a dose-dependent manner were decreased. In addition, hematoxylin-eosin staining showed that liver tissue damage and inflammatory cell infiltration in mice were significantly reduced with increasing doses. Further, oil red staining showed that lipid accumulation in hepatocytes in the low, medium, and high AA group was significantly reduced, with increasing dose. In addition, in the cellular model, real-time reverse transcriptase-polymerase chain reaction (Real-Time RT-PCR) and enzyme-linked immunosorbent assay (ELISA) results showed that AA could alleviate alcohol-induced cellular inflammation, while western blot and immunofluorescence results showed that AA might alleviate alcohol-induced cellular inflammation by inhibiting the nuclear factor-κB (NF-κB) pathway. Conclusion: This study provides multiple lines of evidence that asiatic acid may alleviate alcoholic hepatitis in mice by modulating the NF-κB pathway.
Assuntos
Fígado Gorduroso Alcoólico , Camundongos , Animais , Fígado Gorduroso Alcoólico/tratamento farmacológico , Interleucina-1beta , NF-kappa B , Interleucina-6 , Fator de Necrose Tumoral alfa , Alanina Transaminase , Silibina , Amarelo de Eosina-(YS) , Hematoxilina , Farmacologia em Rede , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Etanol , Inflamação/tratamento farmacológico , Aspartato Aminotransferases , Colesterol , Lipídeos , FígadoRESUMO
Alcoholic beverages are widely consumed all over the world, but continuous ethanol exposure leads to hepatic steatosis that, without proper treatment, will later develop into severe liver disorders. In this study, we investigated the potential protective effect of tangeretin, a flavonoid derived from citrus peel, against alcoholic fatty liver. The in vivo effects of tangeretin were analyzed by oral intake in a chronic-binge alcohol feeding C57BL/6j mouse model, while the underlying mechanism was explored by in vitro studies performed on ethanol-treated hepatic AML-12 cells. Ethanol feeding increased the serum alanine aminotransferase and aspartate aminotransferase levels, the liver weight, and the serum and liver triacylglycerol contents, whereas 20 and 40 mg/kg tangeretin treatment promoted a dose-dependent suppression of these effects. Interestingly, tangeretin prevented increases in the liver oxidative stress level and protected the hepatocyte mitochondria from ethanol-induced morphologic abnormalities. A mechanistic study showed that 20 µM tangeretin treatment activated mitophagy through an AMP-activated protein kinase (AMPK)-uncoordinated 51-like kinase 1 (Ulk1) pathway, thereby restoring mitochondria respiratory function and suppressing steatosis. By contrast, blocking the AMPK-Ulk1 pathway with compound C reversed the hepatoprotective effect of tangeretin. Overall, tangeretin activated mitophagy and protected against ethanol-induced hepatic steatosis through an AMPK-Ulk1-dependent mechanism.
Assuntos
Fígado Gorduroso Alcoólico , Fígado Gorduroso , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Etanol/efeitos adversos , Etanol/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/prevenção & controle , Flavonas , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MitofagiaRESUMO
Inflammation plays an important role in the progression of alcohol-related liver disease (ALD). UDP-P2Y6 signaling is involved in many human diseases. The purinergic P2Y6 receptor, an important regulator of inflammation and phagocytosis, has attracted attention, but its role in alcoholic steatohepatitis remains unclear. Here, we found that P2Y6 levels were significantly elevated in Kupffer cells in the livers of mice with alcoholic steatohepatitis and ethanol (EtOH)-induced RAW264.7 cells. In this study, mice with alcoholic steatohepatitis were intraperitoneally injected with MRS2578, a specific inhibitor of the P2Y6 receptor, and P2Y6 was silenced in EtOH-induced RAW264.7 cells. We found a marked improvement in steatosis and inflammation in the livers of mice with alcoholic steatohepatitis and EtOH-induced RAW264.7 cells. However, P2Y6 activation in vivo and overexpression in vitro showed contrasting results. In addition, the expression of phospho-p38 mitogen-activated protein kinase (p-p38 MAPK), a phosphorylated protein in the p38 MAPK signaling pathway, was significantly altered after P2Y6 silencing or overexpression in vitro. P2Y6 can induce the activation of the p38 MAPK signaling pathway by mediating the calcium influx, whereas inhibition of the expression of P2Y6 can block the inflammatory process to some extent and thus improve the inflammatory response. The results of this study suggested that targeting P2Y6 signaling may be a potentially effective strategy for the treatment of alcoholic steatohepatitis.
Assuntos
Fígado Gorduroso Alcoólico , Células de Kupffer , Animais , Etanol/farmacologia , Fígado Gorduroso Alcoólico/tratamento farmacológico , Inflamação , Camundongos , Receptores Purinérgicos P2 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid oxidation (FAO). Usually, very-long chain fatty acids are first activated by acyl-CoA synthetase (ACS) to generate acyl-CoA for oxidation by acyl-CoA oxidase (ACOX) in peroxisomes, and the resultant shorter chain fatty acids will be further oxidized in mitochondria. ACS long-chain family member 4 (ACSL4) preferentially uses arachidonic acid (AA) as substrates to synthesize arachidonoyl-CoA. Arachidonoyl-CoA is usually esterified into phospholipids. When AA is released by phospholipase A2 (PLA2) from phospholipids, it will be used for prostaglandin synthesis by cyclooxygenases (COX). In this study, when PPARα agonist WY-14,643 was mixed in liquid Lieber-DeCarli ethanol or control diets and fed to mice, liver PLA2, COX-2, and ACOX1 were induced but ACSL4 was inhibited, suggesting that AA released by PLA2 from phospholipid will be metabolized to prostaglandin via COX-2 instead of being synthesized into acyl-CoA by ACSL4. However, liver prostaglandin E2 (PGE2), a major component of prostaglandin, was not increased with the induced COX-2 but decreased by WY-14,643. ACOX1 specific inhibitor mixed in the liquid diets restored both the WY-14,643-suppressed liver TG and PGE2, but COX-2 specific inhibitor celecoxib mixed in the liquid diets reversed the WY-14,643-suppressed liver TG but not liver PGE2 contents. These results suggest that induction of PLA2, COX-2 and ACOX1 orchestrates to increase oxidation of AA/PGE2, which constitutes one new mechanism by which PPARα induces peroxisomal FAO and inhibits ethanol-induced liver fat accumulation.
Assuntos
Acil-CoA Oxidase , Ciclo-Oxigenase 2 , Fígado Gorduroso Alcoólico , PPAR alfa , Fosfolipases A2 , Pirimidinas , Acil-CoA Oxidase/metabolismo , Animais , Coenzima A/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Camundongos , PPAR alfa/agonistas , PPAR alfa/metabolismo , Peroxissomos/efeitos dos fármacos , Peroxissomos/metabolismo , Fosfolipases A2/metabolismo , Fosfolipídeos/metabolismo , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: With the development of economy and increased workload, chronic a high-fat/alcohol diet intake may lead to alcoholic fatty liver disease (AFLD), which is considered as a crucial health problem worldwide. E Se tea is produced of the leaves and leaf buds of Malus toringoides (Rehd.) Hughes in Tibet and has human health benefits with anti-hyperglycemia, hypertension, and hyperlipidemia effects. PURPOSE: The objective of this work was to investigate the protective effect of aqueous-ethanol and hot-water extracts of E Se tea against chronic high-fat/alcohol diet induced AFLD rats. METHODS: Firstly, to determine the chemical profiling of E Se tea extracts, UHPLC-ESI-HRMS analysis was conducted. Secondly, Sprague-Dawley male rats were used to establish the AFLD animal model by feeding with high-fat/alcohol diet. The animals were treated with E Se tea extracts for 12 weeks. Serum parameters were determined, histologic sections were prepared, and activities of enzymes related to inflammatory response and lipid metabolism imbalance were analyzed. The underlying mechanisms of E Se tea extracts alleviating AFLD were analyzed by immunofluorescence staining and Western blotting analysis. Lastly, key targets of 11-MT against AFLD were verified through molecular docking. RESULTS: In this study, seven main compounds were confirmed or tentatively identified in E Se tea extracts by UHPLC-ESI-HRMS. The results revealed that both the extracts could reverse histopathological steatotic alternation of the liver and reduced the activity of liver damage markers (ALT, AST). E Se tea extracts mitigated oxidative stress by inhibiting CYP2E1 protein and lipid peroxidation parameters (MDA), but enhancing the endogenous antioxidants (CAT, GSH, SOD). Moreover, E Se tea extracts ameliorated inflammation by restraining the activation of NF-κB, consequently releasing the expression of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, COX-2 and iNOS). Subsequently, E Se tea extracts reduced hepatocyte apoptosis by increasing capase-9, caspase-3 and Bax protein expression but decreasing Bcl-2 protein expression. Furthermore, E Se tea extracts improved metabolism imbalance by stimulating AMPK/SREBP1/FAS and PPAR-α/CPT1 signaling pathway by regulating lipid metabolism parameters (TC, TG, HDL-C, LHD-C). Furthermore, molecular docking results indicated that 7 chemical constituents of E Se tea extracts had strong docking affinity with 4 key target proteins (AMPK, PPAR-α, NF-кB and Caspase-9). CONCLUSION: E Se tea ameliorated AFLD through ameliorating inflammatory response, apoptosis, and lipid metabolism imbalance.