High-fat Diet-induced Liver Injury Research Articles

Alleviating effects of guar gum on high-fat diet-induced liver injury in common carp (Cyprinus carpio)

This research aimed to determine the effect of dietary guar gum inclusion in high-lipid diets on the liver health of common carp (Cyprinus carpio). Four high-fat diets (10 % crude lipid) containing 0 % (HF), 0.3 % (HFG0.3), 1 % (HFG1), and 3 % (HFG3) of guar gum and a normal-lipid diet (5 % crude lipid; Control) were formulated. The tested diets were evenly and randomly distributed to fifteen tanks, with each tank containing thirty fish (4.53 ± 0.05 g). Fish were fed until apparent satiation for eight weeks. Compared to HF, diets HFG0.3, HFG1, and HFG3 significantly improved feed efficiency, with the HFG0.3 diet enhancing weight gain rate and specific growth rate. The results indicated that HF induced gut dysbiosis, hepatic lipid accumulation, oxidative stress, inflammation, and disturbance in hepatic lipid and cholesterol metabolism. Compared to the HF diet, diets HFG0.3, HFG1, and HFG3 substantially decreased hepatic lipid accumulation and malonaldehyde content, increased catalase activity and the expression of AMP-activated protein kinase (AMPKα2), peroxisomal proliferator-activated receptor alpha (PPARα), cholesterol 7alpha-hydroxylase, and decreased the expression of interleukin-1β (IL-1β). Moreover, the HFG0.3 and HFG1 diets dramatically increased nuclear factor erythroid 2-related factor 2 and liver X receptor expression and decreased protein carbonyl contents and expression of IL-8, nuclear factor kappa B (NF-κB p65), and tumor necrosis factor α. Furthermore, the HFG1 diet significantly increased carnitine palmitoyltransferase 1 and peroxisomal proliferator-activated receptor gamma coactivator 1 expression and reduced expression levels of fibroblast growth factor 19, farnesoid X receptor, and sterol regulatory element-binding protein type 1. The linear discriminant analysis effect size (LEfSe) analysis showed that HFG 0.3 and HFG1 substantially increased the enrichment of beneficial microbiota (e.g., lactic acid bacteria, Cetobacterium, and Fusobacterial) and decreased the enrichment of harmful microbiota (e.g., Proteobacteria, Acinetobacter, and Pseudomonas) compared to HF. These results suggested that guar gum can mitigate high-fat diet-induced liver damage in fish.

Hepatic changes following a high-fat diet: effects of Cornus mas and gold nanoparticles phytoreduced with Cornus mas on oxidative stress, inflammation, and histological damage.

High fat diet (HFD) can lead to liver injury, through oxidative stress and inflammation. The use of natural compounds with antioxidant and anti-inflammatory properties can have a protective potential. We aimed to investigate the effects of Cornus mas (CM) and gold nanoparticles phytoreduced with CM (GNPsCM) on hepatic alterations induced by HFD in rats. Female Sprague Dawley rats were randomly divided into four groups: control, HFD, HFD +CM and HFD + GNPsCM. The high fat diet was administered for 32 weeks and CM and GNPsCM were administered for 4 weeks after the HFD period. The high fat diet induced oxidative stress in liver, with lipid peroxidation and decreased antioxidant capacity, inflammation and minimal histological alterations. The administration of CM and GNPsCM reduced lipid peroxidation produced by HFD and increased antioxidant potential in liver homogenates, while increasing inflammatory markers. Histological alterations were slightly improved by the intervention of compounds, and hyaluronic acid content of the liver without statistical significance as compared to HFD group. These findings support the potential of these treatments in addressing liver oxidative stress, mitigating liver damage induced by a high-fat diet. This investigation sheds light on the oxidative stress dynamics and histological alterations associated with high-fat diet-induced liver injury, contributing to our understanding of potential therapeutic interventions.

Receptor-interacting protein 1 and 3 kinase activity are required for high-fat diet induced liver injury in mice.

The RIP1-RIP3-MLKL-mediated cell death pathway is associated with progression of non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Previous work identified a critical role for MLKL, the key effector regulating necroptosis, but not RIP3, in mediating high fat diet-induced liver injury in mice. RIP1 and RIP3 have active N-terminus kinase domains essential for activation of MLKL and subsequent necroptosis. However, little is known regarding domain-specific roles of RIP1/RIP3 kinase in liver diseases. Here, we hypothesized that RIP1/RIP3 kinase activity are required for the development of high fat diet-induced liver injury. Rip1K45A/K45A and Rip3K51A/K51A kinase-dead mice on a C57BL/6J background and their littermate controls (WT) were allowed free access to a diet high in fat, fructose and cholesterol (FFC diet) or chow diet. Both Rip1K45A/K45A and Rip3K51A/K51A mice were protected against FFC diet-induced steatosis, hepatocyte injury and expression of hepatic inflammatory cytokines and chemokines. FFC diet increased phosphorylation and oligomerization of MLKL and hepatocyte death in livers of WT, but not in Rip3K51A/K51A, mice. Consistent with in vivo data, RIP3 kinase deficiency in primary hepatocytes prevented palmitic acid-induced translocation of MLKL to the cell surface and cytotoxicity. Additionally, loss of Rip1 or Rip3 kinase suppressed FFC diet-mediated formation of crown-like structures (indicators of dead adipocytes) and expression of mRNA for inflammatory response genes in epididymal adipose tissue. Moreover, FFC diet increased expression of multiple adipokines, including leptin and plasminogen activator inhibitor 1, in WT mice, which was abrogated by Rip3 kinase deficiency. The current data indicate that both RIP1 and RIP3 kinase activity contribute to FFC diet-induced liver injury. This effect of RIP1 and RIP3 kinase deficiency on injury is consistent with the protection of Mlkl-/- mice from high fat diet-induced liver injury, but not the reported lack of protection in Rip3-/- mice. Taken together with previous reports, our data suggest that other domains of RIP3 likely counteract the effect of RIP3 kinase in response to high fat diets.

Dendrobium huoshanense Polysaccharide Improves High-Fat Diet Induced Liver Injury by Regulating the Gut-Liver Axis.

Dendrobium huoshanense is an important Traditional Chinese medicine that thickens the stomach and intestines. Its active ingredient Dendrobium huoshanense polysaccharide (DHP), was revealed to relieve the symptoms of liver injury. However, its mechanism of action remains poorly understood. This study aimed to investigate the mechanism of DHP in protecting the liver. The effects of DHP on lipid levels, liver function, and intestinal barrier function were investigated in mice with high-fat diet-induced liver damage. Changes in the gut flora and their metabolites were analyzed using 16S rRNA sequencing and metabolomics. The results showed that DHP reduced lipid levels, liver injury, and intestinal permeability. DHP altered the intestinal flora structure and increased the relative abundance of Bifidobacterium animalis and Clostridium disporicum. Furthermore, fecal metabolomics revealed that DHP altered fecal metabolites and significantly increased levels of gut-derived metabolites, spermidine, and indole, which have been reported to inhibit liver injury and improve lipid metabolism and the intestinal barrier. Correlation analysis showed that spermidine and indole levels were significantly negatively correlated with liver injury-related parameters and positively correlated with the intestinal species B. animalis enriched by DHP. Overall, this study confirmed that DHP prevented liver injury by regulating intestinal microbiota dysbiosis and fecal metabolites.

Exercise intervention improves mitochondrial quality in non-alcoholic fatty liver disease zebrafish.

Recent reports indicate that mitochondrial quality decreases during non-alcoholic fatty liver disease (NAFLD) progression, and targeting the mitochondria may be a possible treatment for NAFLD. Exercise can effectively slow NAFLD progression or treat NAFLD. However, the effect of exercise on mitochondrial quality in NAFLD has not yet been established. In the present study, we fed zebrafish a high-fat diet to model NAFLD, and subjected the zebrafish to swimming exercise. After 12 weeks, swimming exercise significantly reduced high-fat diet-induced liver injury, and reduced inflammation and fibrosis markers. Swimming exercise improved mitochondrial morphology and dynamics, inducing upregulation of optic atrophy 1(OPA1), dynamin related protein 1 (DRP1), and mitofusin 2 (MFN2) protein expression. Swimming exercise also activated mitochondrial biogenesis via the sirtuin 1 (SIRT1)/ AMP-activated protein kinase (AMPK)/ PPARgamma coactivator 1 alpha (PGC1α) pathway, and improved the mRNA expression of genes related to mitochondrial fatty acid oxidation and oxidative phosphorylation. Furthermore, we find that mitophagy was suppressed in NAFLD zebrafish liver with the decreased numbers of mitophagosomes, the inhibition of PTEN-induced kinase 1 (PINK1) - parkinRBR E3 ubiquitin protein ligase (PARKIN) pathway and upregulation of sequestosome 1 (P62) expression. Notably, swimming exercise partially recovered number of mitophagosomes, which was associated with upregulated PARKIN expression and decreased p62 expression. These results demonstrate that swimming exercise could alleviate the effects of NAFLD on the mitochondria, suggesting that exercise may be beneficial for treating NAFLD.

Dietary Sodium Butyrate Supplementation Alleviates High-Fat Diet-Induced Liver Injury by Activating Nrf2 in Common Carp (Cyprinus carpio)

Dietary Sodium Butyrate Supplementation Alleviates High-Fat Diet-Induced Liver Injury by Activating Nrf2 in Common Carp (Cyprinus carpio)

The effects of scoparone on alcohol and high-fat diet-induced liver injury revealed by RNA sequencing

Scoparone (SCO) has a wide range of pharmacological activities, especially antioxidant and lipid-lowering ones. The purpose of this study was to investigate the effect of SCO on alleviating liver injury induced by alcohol and high-fat diet (HFD) in mice. The pathomorphology, biochemical indices, lipid accumulation, alcohol metabolism, oxidative stress and inflammatory response were examined. RNA sequencing analysis was performed on liver tissues to identify differentially expressed genes (DEGs) and signaling pathways, thus elucidating the mechanism of SCO in protecting the liver. Finally, some of the DEGs were validated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The results showed that SCO had significant hepatoprotective effects, which could inhibit lipid accumulation, improve alcohol metabolism, reduce oxidative stress and inhibit inflammatory response. RNA sequencing results showed that 1208 genes were differentially expressed in liver tissues of mice treated with alcohol and HFD, while 2143 genes were significantly changed after SCO intervention. These DEGs were mainly involved in metabolism of xenobiotics by cytochrome P450, fatty acid (triglyceride) metabolism, and cholesterol synthesis pathways. In addition, the results of qRT-PCR and Western blot were consistent with the RNA sequencing. SCO can alleviate liver injury induced by alcohol and HFD in mice, and its mechanism may be related to regulating alcohol metabolism and lipid metabolism pathways.

Protective effects of maslinic acid on high fat diet-induced liver injury in mice

AimsDue to the prevalence of high-fat diets and lack of exercise, diseases related to nutrient metabolism such as nonalcoholic fatty liver disease (NAFLD) have become one of the reasons causes endangering human liver health. Maslinic acid (MA) is a pentacyclic triterpenoid acid that is abundant in fruits such as hawthorn and jujube. In this study, we investigated the effect of MA on NAFLD to inform the development of dietary supplements for the treatment and prevention of NAFLD. Materials and methodsThe NAFLD model was established by feeding mice a high-fat diet (HFD). HEPG2 cells were treated with oleic acid and used as a cell culture model. Testing kits, haematoxylin and eosin staining, oil red O staining, western blotting, and immunofluorescence were performed with in vivo and in vitro experiments. Key findingsThe current study revealed that MA significantly reduced liver weight, body weight and serum lipid levels, and protected against liver steatosis and injury induced by a HFD. MA increased the expression of Beclin1, ATG1, and Bcl-2 mRNA and protein while decreasing the expression of TNF-α and IL-1β, caspase-3 and Bax mRNA and protein. Beclin1, and ATG1 were obviously increased, and the mRNA and protein expression of TNF-α and IL-1β were obviously reduced, the mRNA and protein expression of Caspase-3 and Bax were obviously reduced, and the mRNA and protein expression of Bax were obviously increased by MA. SignificanceMA reduces the content of fat in the liver cells of NAFLD mice through lipophagy activitiy and reduces inflammation and apoptosis injury.

Effects of theaflavin-3, 3'-digallate on high-fat diet-induced liver injury in mice and its mechanism

Effects of theaflavin-3, 3'-digallate on high-fat diet-induced liver injury in mice and its mechanism

AP39 ameliorates high fat diet-induced liver injury in young rats via alleviation of oxidative stress and mitochondrial impairment

Non-alcoholic fatty liver disease (NAFLD) is a complication of childhood obesity and an oxidative stress-related multisystem disease. A mitochondria-targeting hydrogen sulfide (H2S) donor AP39 has antioxidant property, while the mechanism underlying the function of AP39 on pediatric NAFLD remains undefined. Here, 3-week-old SD rats were received a high-fat diet (HFD) feeding and injected with AP39 (0.05 or 0.1 mg/kg/day) via the tail vein for up to 7 weeks. AP39 reduced weight gain of HFD rats and improved HFD-caused liver injury, as evidenced by reduced liver index, improved liver pathological damage, decreased NAFLD activity score, as well as low alanine transaminase (ALT) and aspartate transaminase (AST) activities. AP39 also reduced serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) concentrations but increased high-density lipoprotein-cholesterol (HDL-C). Moreover, AP39 prevented reactive oxygen species (ROS) generation, reduced MDA content and increased glutathione (GSH) level and superoxide dismutase (SOD) activity. Furthermore, AP39 increased H2S level, protected mitochondrial DNA (mtDNA), reduced mitochondrial swelling, and restored mitochondrial membrane potential (MMP) alteration. Notably, AP39 diminished HIF-1α mRNA and protein level, possibly indicating the alleviation in mitochondrial damage. In short, AP39 protects against HFD-induced liver injury in young rats probably through attenuating lipid accumulation, oxidative stress and mitochondrial dysfunction.

Pediococcus pentosaceus PP04 improves high-fat diet-induced liver injury by the modulation of gut inflammation and intestinal microbiota in C57BL/6N mice.

In this study, Pediococcus pentococcus PP04 (PP04) isolated from the Northeast pickled cabbage was given to C57BL/6N mice for eight weeks, aiming to investigate the ameliorative effects of PP04 on liver injury induced by a high-fat diet. The western blot results suggested that PP04 ameliorated the increase of intestinal permeability by dramatically increasing the expressions of tight junction proteins, such as Occludin, Claudin-1 and ZO-1, which decreased hepatic lipopolysaccharides (LPS), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations to effectively alleviate the liver injury. Furthermore, PP04 relieved the high-fat diet-caused gut inflammation by the NF-κB/Nrf2 signaling pathway, which regulated the expression of inflammatory cytokines and antioxidants, to positively improve the liver injury. In addition, the 16S rDNA sequencing results inferred that PP04 had the potential to rebalance intestinal flora disorders through regulating the relative abundance of inflammation and obesity-related bacteria in mice.

Effects of taraxasterol against ethanol and high-fat diet-induced liver injury by regulating TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways

Studies have reported that taraxasterol (TAR) is effective in the treatment of immune liver injury and alcoholic liver injury. The mechanism of action is mainly related to the inhibition of inflammation. To determine the key molecular mechanisms for the effect of TAR on alleviating ethanol and high-fat diet-induced liver injury, pathological morphology, biochemistry, oxidative stress, inflammatory response and lipid metabolism were examined. Our results showed that TAR could inhibit ethanol-induced hepatocyte death or lipid accumulation, and suppress oxidative stress, inflammatory response and lipid metabolism disorders. More specifically, ethanol-induced TLR-4 and MyD88 inflammatory response were down-regulated, when treated with TAR. Production of CYP2E1, Nrf2 and HO-1, which produced in response to increased oxidative stress, were regulated in TAR treated, ethanol-induced hepatocytes. In summary, TAR could inhibit the inflammatory response and oxidative stress, which was related to the regulation of TAR on TLR-4/MyD88/NF-κB and Nrf2/HO-1 pathways.

Native polypeptide vglycin prevents nonalcoholic fatty liver disease in mice by activating the AMPK pathway

• Vglycin ameliorates HFD induced liver injury, inflammation and insulin resistance. • Vglycin prevents HepG2 cells apoptosis from OA induced mitochondrial dysfunction. • Vglycin prevents NAFLD by inhibiting the AMPK mediated liver-fat accumulation. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, and it has no effective treatment. We previously reported that the native polypeptide vglycin (purified from soybean) has a beneficial role in regulating glucose homeostasis in diabetic rats. In this study, we investigated the preventive effects of vglycin and possible mechanisms of action in hepatic steatosis using a high-fat diet (HFD)-induced mouse model. The results revealed that vglycin decreased the body weight, liver weight, Lee’s index, and plasma triglyceride level in HFD-fed C57BL/6J mice. Furthermore, it prevented liver injury, inflammation and insulin resistance by inhibiting fat accumulation in liver. These beneficial effects of vglycin are probably attributable to the activation of the AMP-activated protein kinase (AMPK) pathway and the down-regulation of fatty acid synthase (FAS). Therefore, vglycin holds promise as an oral drug for the prevention of NAFLD.

Salidroside alleviates lipotoxicity-induced cell death through inhibition of TLR4/MAPKs pathway, and independently of AMPK and autophagy in AML-12 mouse hepatocytes

• Salidroside alleviates hepatocellular death in response to lipotoxicity. • Salidroside inhibits lipotoxicity-induced oxidative stress and mitochondrial injury. • Salidroside improves lipotoxicity-induced inflammation in hepatocytes. • Salidroside inhibits lipotoxicity-activated TLR4/MAPKs pathways in hepatocytes. • TLR4 inhibition contributes to salidroside-reduced lipids deposition in hepatocytes. Lipotoxicity plays a detrimental role in the pathogenesis of non-alcoholic fatty liver diseases (NAFLD). Salidroside (Sal), a phenylpropanoid glycoside extracted from Rhodiola rosea L, conferred resistance to high-fat diet-induced liver injury. However, the underlying mechanisms are still unclear. This study aimed at investigating Sal-inhibited lipotoxicity and clarify its potential mechanisms. Our study indicated that Sal significantly reversed palmitic acids-induced injury in dose-dependent manner in AML-12 mouse hepatocytes, accompanied with improvement of oxidative stress and mitochondrial damage. Mechanistic analysis revealed that Sal protected hepatic lipotoxicity via reversing TLR4/MAPKs (including JNK, p38, and ERk1/2) and p53 activation, independent from autophagy, AMPK, and Akt pathways. Moreover, TLR4 inhibition also contributed to salidroside-reduced lipids deposition. In sum, this research clearly demonstrated the protective effects of Sal against lipotoxicity-induced hepatic cell death, which was mediated by downregulation of TLR4/MAPKs pathways in hepatocytes. We conclude that Sal is a potential candidate for the treatment of NAFLD.

JIP3 knockout protects mice against high fat diet-induced liver injury

Multiple pathways contribute to nonalcoholic fatty liver disease (NAFLD) in response to high fat diets (HFD). A homolog of mammalian JNK-interacting protein 3 (JIP3), also known as JSAP-1, activates different components in various signaling pathways to modulate cellular processes. The purpose of this study was to examine the role of JIP3 in obesity-related pathologies pathway. Wild-type (WT) C57BL/6 and JIP3-knockout (JIP3−/−) mice were randomized to chow or HFD. HFD-fed WT mice increased hepatic JIP3 expression. Mice lacking JIP3 exhibited reduced weight gain, hepatic steatosis, insulin resistance, lipid accumulation, oxidative stress and inflammatory response in mice fed a HFD, which were, importantly, dependent on various signaling pathways. Lipogenesis-linked pathway was inhibited in JIP3−/− mice after HFD, while PPARα/γ were increased. Additionally, JIP3−/− inhibited hepatic oxidative stress, evidenced by down-regulation of total reactive oxygen species (ROS), H2O2, O2.-, malondialdehyde (MDA), xanthine oxidase (XO), inducible nitric oxide synthase (iNOS), and up-regulation of superoxide dismutase (SOD) and total antioxidant capacity (TAC) in mice after HFD feeding, which might be related to nuclear respiratory factor 2 (Nrf-2) pathway activation. Further, inflammatory response was blocked in JIP3−/− mice fed with HFD. The process might be attributed to the suppression of toll-like receptors (TLRs), p-nuclear factor kappa B (NF-κB) and p-c-Jun-N-terminal kinase (JNK). Thus, JIP3 absence is associated with decreased lipogenesis, oxidative stress and inflammation, supplying a new target for NAFLD treatment.

Histidine-alleviated hepatocellular death in response to 4-hydroxynonenal contributes to the protection against high-fat diet-induced liver injury

4-Hydroxynonenal (4-HNE) is a critical lipid peroxidation product induced by oxidative stress that has been implicated in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We previously reported that histidine ameliorated oxidative stress in both obese women and high-fat diet (HFD)-induced rats. However, the mechanism of histidine against liver injury in NAFLD remains unclear. This study aimed to investigate the effect of histidine supplementation on alleviating HFD-induced liver injury. Histidine relieved both HFD-induced liver injury and 4-HNE-induced hepatotoxicity. Histidine acted partly by inhibiting both c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in paralle, while the reactive oxygen species-mediated MAPKs axes were also implicated in the protective role of histidine. Histidine reversed 4-HNE-protein adducts formation in both rat liver and hepatocytes. These findings suggest that increased histidine intake may be a potential therapeutic choice for NAFLD.

WITHDRAWN: JIP3 deficiency protects mice from high fat diet-induced liver injury

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Endogenous catalase delays high-fat diet-induced liver injury in mice.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in parallel with worldwide epidemic of obesity. Reactive oxygen species (ROS) contributes to the development and progression of NAFLD. Peroxisomes play an important role in fatty acid oxidation and ROS homeostasis, and catalase is an antioxidant exclusively expressed in peroxisome. The present study examined the role of endogenous catalase in early stage of NAFLD. 8-week-old male catalase knock-out (CKO) and age-matched C57BL/6J wild type (WT) mice were fed either a normal diet (ND: 18% of total calories from fat) or a high fat diet (HFD: 60% of total calories from fat) for 2 weeks. CKO mice gained body weight faster than WT mice at early period of HFD feeding. Plasma triglyceride and ALT, fasting plasma insulin, as well as liver lipid accumulation, inflammation (F4/80 staining), and oxidative stress (8-oxo-dG staining and nitrotyrosine level) were significantly increased in CKO but not in WT mice at 2 weeks of HFD feeding. While phosphorylation of Akt (Ser473) and PGC1α mRNA expression were decreased in both CKO and WT mice at HFD feeding, GSK3β phosphorylation and Cox4-il mRNA expression in the liver were decreased only in CKO-HF mice. Taken together, the present data demonstrated that endogenous catalase exerted beneficial effects in protecting liver injury including lipid accumulation and inflammation through maintaining liver redox balance from the early stage of HFD-induced metabolic stress.

Receptor interacting protein 3 protects mice from high-fat diet-induced liverinjury.

Absence of RIP3, a key mediator of necroptosis, exacerbated HFD-induced liver injury, associated with increased inflammation and hepatocyte apoptosis, as well as early fibrotic responses; these findings indicate that shifts in the mode of hepatocellular death can influence disease progression and have therapeutic implications because manipulation of hepatocyte cell death pathways is being considered as a target for treatment of nonalcoholic fatty liver disease. (Hepatology 2016;64:1518-1533).

Juglone prevents metabolic endotoxemia-induced hepatitis and neuroinflammation via suppressing TLR4/NF-κB signaling pathway in high-fat diet rats

Juglone as a natural production mainly extracted from green walnut husks of Juglans mandshurica has been defined as the functional composition among a series of compounds. It showed powerful protective effect in various diseases by inhibiting inflammation and tumor cells growth. However, studies on its anti-inflammatory effect based on high-fat diet-induced hepatitis and neuroinflammation are still not available. In this regard, we first investigated whether juglone suppresses high-fat diet-stimulated liver injury, hypothalamus inflammation and underlying mechanisms by which they may recover them. SD rats were orally treated with or without high-fat diet, 0.25 mg/kg or 1 mg/kg juglone for 70 days. Subsequently, blood, hypothalamus and liver tissue were collected for different analysis. Also, the primary astrocytes were isolated and used to analyze the inhibitory effect of juglone in vitro. Analysis of inflammatory cytokines declared that the inhibition of TNF-α, IL-1β and IL-6 could be carried by juglone in response to high-fat diet rats. Meanwhile, TLR4 expression and NF-kappa activity also have been confirmed to be the key link in the development of hepatitis and nerve inflammation. The activation was significantly suppressed in treatment group as compared with model. These results indicated that juglone prevents high-fat diet-induced liver injury and nerve inflammation in mice through inhibition of inflammatory cytokine secretion, NF-kappa B activation and endotoxin production.