HFD-induced Nonalcoholic Fatty Liver Disease Research Articles

Mulberry galacto-oligosaccharides ameliorates non-alcoholic fatty liver disease in mice induced by a high-fat diet

A type of oligosaccharide named mulberry galacto-oligosaccharides (MGO), was isolated from mulberry with a galactose-only, weighs 987 Da and displays diverse biological properties. The objective of this work was to investigate the protective effects of MGO in non-alcoholic fatty liver disease (NAFLD) mice. The results showed that MGO can reduce the body weight and liver weight of NAFLD mice, and reduce the levels of NEFA, TG, TC and LDL-C in serum and liver as well as the activities of AST and ALT. Increase HDL-C content, SOD, and GSH activity in serum and improve pathological damage. MGO regulates the AMPK lipid metabolism pathway, upregulates the expression of ATGL, downregulates the expression of SREBP-1, inhibits lipogenesis, and promotes lipolysis. MGO alleviates liver function damage in NAFLD mice, improves blood lipids, liver metabolism, and increases the body’s antioxidant capacity, suggesting MGO potential as a dietary supplement and functional food to combat HFD-induced NAFLD.

Effect of rapamycin on hepatic metabolomics of non-alcoholic fatty liver rats based on non-targeted platform

Rapamycin (Rapa) is an inhibitor of mTOR complex, and its therapeutic effect on liver function was examined in non-alcoholic fatty liver disease (NAFLD) rats here. And the possible mechanism of Rapa in NAFLD was preliminarily elucidated based on the non-targeted metabolomics analysis. Adult male SD rats were fed with a high-fat and high-cholesterol diet (HFD) to establish NAFLD model. For Rapa group, 0.8 mg/(kg.d) Rapa was given to the HFD rats. Ultra-performance liquid chromatography and Q-Tof-mass spectrometry (UPLC and Q-TOF/MS) analysis were applied for the identification of metabolites in the serum of rats, which were annotated using Kyoto Encyclopedia of Genes and Genomes (KEGG). NAFLD rats presented with disturbed liver function, lipid metabolism and oxidative stress, but Rapa exerted a mitigating influence on the disorders. The metabolite profile data identified 579 metabolites that varied remarkably between the Rapa and HFD groups, with the main classes of amino acids and peptides, benzene, lipids and fatty acids. The differential metabolites were mainly involved in biosynthesis of cofactors, bile secretion, and glycerophospholipid metabolism were mainly enriched. In conclusion, Rapa has a potential protective effect against HFD-induced NAFLD, its hepatoprotective effect may achieved through mediating bile secretion and glycerophospholipid metabolism.

Integrative transcriptomics and lipidomics unravels the amelioration effects of Radix Bupleuri on non-alcoholic fatty liver disease

Ethnopharmacological relevanceRadix Bupleuri (Bupleurum chinense DC.) is the most commonly used traditional Chinese medicine (TCM) for the treatment of liver diseases. While the effects of Radix Bupleuri (BR) on lipid-lowering and liver protection have been established, its role in the development of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet remains unclear. Aim of the studyThe objective of this study was to evaluate the alleviation effects of the active fraction of BR on NAFLD in vivo and to explore the underlying mechanisms through an analysis of liver transcriptome and lipidomics. Materials and methodsThe NAFLD model was established in SD rats by administering a high-fat diet (HFD) for 8 weeks. Subsequently, the NAFLD model rats were continuously gavaged with different polarity fractions of BR (25 g/kg/d) and melatonin (MT) (30 mg/kg/d) for an additional 6 weeks to assess therapeutic effects. The potential mechanism of the low polarity fraction of BR (LBR) in treating NAFLD was investigated through hepatic transcriptome analysis, non-targeted lipidomics, RT-qPCR, protein-protein interaction (PPI) network construction, molecular docking, and Western blotting, aiming to elucidate the underlying mechanisms by which LBR may ameliorate NAFLD. ResultsThese results demonstrated that LBR significantly alleviated the effects of HFD-induced NAFLD, as evidenced by reductions in body weight (BW), liver weight (LW), and epididymal fat weight (EFW) compared to model rats and other polarity fractions of BR. Furthermore, LBR notably down-regulated serum and liver levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), while up-regulating high-density lipoprotein cholesterol (HDL-C) in serum. Mechanistically, liver transcriptome analysis indicated that fatty acid metabolism may be a crucial pathway for the improvement of NAFLD following LBR treatment. Lipidomics data suggested that LBR can modulate the metabolic profile in NAFLD rats. Enrichment analysis revealed that glycerophospholipid and glycerolipid metabolism might be key pathways involved in the development of NAFLD. RT-qPCR analysis demonstrated that LBR could regulate the expression of lipid-related genes in these critical pathways. Additionally, Spearman correlation analysis showed a strong relationship between lipid metabolic biomarkers, pathological indices, and lipid-related genes. Moreover, protein-protein interaction (PPI) network and molecular docking analyses identified seven key targets with six ingredients of LBR exhibiting good binding capacity (< -5.0 kcal/mol). Finally, Western blotting analysis indicated that LBR up-regulates the expression levels of PPARα, CPT1, and FABP1 while down-regulating the expression levels of SREBF1 and SCD1, thereby improving metabolism and exerting a lipid-lowering effect. ConclusionIn conclusion, the present research elucidated the lipid-lowering mechanisms of the active fractions of BR. Both BR and LBR presented themselves as promising candidates for the development of novel pharmacological agents targeting NAFLD. LBR effectively ameliorated lipid disturbances associated with HFD-induced NAFLD by modulating the metabolism of fatty acids, cholesterol, glycerolipid, and glycerophospholipids. Consequently, LBR held significant potential for development as an effective lipid-lowering therapeutic.

Hesperitin prevents non-alcoholic steatohepatitis by modulating mitochondrial dynamics and mitophagy via the AMPKα-Drp1/PINK1-Parkin signaling pathway

Non-alcoholic fatty liver disease (NAFLD) is becoming a global public health burden, yet effective therapeutic strategies are notably lacking. NAFLD development may be mediated by mitochondrial dysfunction, according to new research. Producing mitochondrial regulators from plant-based substances to treat mitochondrial dysfunction is an appealing approach to treating NAFLD. Hesperetin (HES) is a flavonoid that is found naturally and is a member of the flavanone family. This study aims to clarify the mechanism of HES in preventing NAFLD which is caused by a high-fat diet (HFD). Serum and liver biochemical parameters, liver histology, lipid profiles, and mitochondrial function were evaluated in HFD-induced NAFLD Sprague-Dawley (SD) rats. HES treatment significantly reduced body weight gain, liver weight, and the liver index, while also improving hepatic steatosis, lipid metabolism disorders, and mitochondrial dysfunction in rats with NAFLD. The mechanism was investigated and confirmed using western blot and real-time quantitative polymerase chain reaction (RT-qPCR). We showed that in the liver of NAFLD rats, HES decreased the expression of dynamic-related protein 1 (Drp1), phosphorylated Drp1 at serine-616 (Drp1-pS616) and induced phosphorylated Drp1 at serine-637 (Drp1-pS637), PTEN-induced kinase 1 (PINK1), and E3 Ubiquitin-Protein Ligase Parkin (Parkin) via an AMP-activated protein kinase alpha (AMPKα)-dependent mechanism. Moreover, HES increased the expression of the mitochondrial fusion proteins mitofusin-2 (Mfn2) and optic atrophy 1 (Opa1) while suppressing the expression of fission protein 1 (Fis1). In this work, we identify a unique mechanism by which HES prevents NAFLD from developing. HES may be an attractive potential therapeutic agent to cure NAFLD.

Shugan Jiangzhi Decoction Alleviates Nonalcoholic Fatty Liver Disease (NAFLD) via Regulating AMPK/PPAR Signaling Pathway

Background: Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Shugan Jiangzhi Decoction (SJD), a traditional Chinese medicine (TCM) formula which consists of six Chinese herbs, has been used for treating hyperlipidemia, obesity, and fatty liver in Guangdong Provincial Hospital of Traditional Chinese Medicine for over twenty years. Objective: This study aims to elucidate the chemical basis and the molecular mechanism of SJD against NAFLD. Methods: The main components of SJD were determined by High Performance Liquid Chromatography (HPLC). Then the high-fat diet (HFD)-induced NAFLD rat model was established. After treatment with different doses of SJD, the body weight of rats was measured weekly. On the last day of the experiments, the hepatic morphology, histopathology changes, and the serum lipid levels were detected. Then techniques of network pharmacology were employed to predict the anti-NAFLD mechanism of SJD. At last, the expression levels of proteins were measured by western blot to verify the mechanism. Results: Nine chemical constituents of SJD were identified from HPLC fingerprint spectrum. For the in vivo experiment, NAFLD rat model was constructed successfully by feeding high-fat diet (HFD) for 8 weeks. The following treatment with SJD for 6 weeks decreased the fatty droplet accumulation in the liver obviously. Meanwhile, the serum level of high-density lipoprotein cholesterol (HDL-c) was increased, while the levels of lowdensity lipoprotein cholesterol (LDL-c), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were decreased after SJD treatment (p &lt; 0.05). The results of network pharmacology indicated that SJD might improve NAFLD via regulating the AMPK/PPAR signaling pathway. Then, the western blot assay confirmed that SJD activated the AMPK/PPAR signaling pathway in the liver of rats. Conclusion: SJD improves HFD-induced NAFLD in rats via AMPK/PPAR signaling pathway. Thus, our study suggests that SJD can serve as a therapeutic agent for the prevention and treatment of NAFLD.

Polysaccharides from Lanzhou Lily Attenuate Nonalcoholic Fatty Liver Disease Modifying the Gut Microbiota and Metabolite Profile.

Nonalcoholic fatty liver disease (NAFLD) is closely related to gut microbiota due to the hepatic portal system, and utilizing natural polysaccharides as prebiotics has become a prospective strategy for treating NAFLD. However, the therapeutic effects and potential molecular mechanisms of Lanzhou Lily polysaccharides (LLP) on NAFLD remains unclear. Therefore, the alleviating effects of LLP on NAFLD induced by high-fat diet (HFD) were investigated. LLP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFD-induced NAFLD mice, as evidenced by decreased serum levels of TG, TC, HDL-C and LDL-C. Furthermore, LLP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. LLP also inhibited the TNF-α and IL-1β expression, thereby reducing levels of hepatic proinflammatory cytokines. Furthermore, LLP restored gut microbiota dysbiosis (up-regulated Bacteroidota, Proteobacteria, Alistipes and Lachnospiraceae abundances, down-regulated Firmicutes, Verrucomicrobiota, Desulfobacterota and Turicibacter abundances), and regulated microbial metabolic pathways such as primary bile acid biosynthesis and amino acid metabolism. In addition, the resultes of Spearman's correlation analysis found that some key metabolites in these metabolic pathways were associated with intestinal microorganisms such as Desulfobacterota, Prevotellaceae-UCG-001, Colidextribacter and Alistipes. Therefore, our study suggests that LLP may has potential applications in the treatment of NAFLD by regulating gut microbiota and its metabolite profile.

Ameliorative effects of Monascus-fermented hawthorn extract on a high-fat diet-induced rat model of non-alcoholic fatty liver disease

ObjectiveThe aim of this study was to elucidate the effects of fermented hawthorn extract on high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats, and explore the possible underlying mechanisms. MethodsA total of 42 male adult Sprague-Dawley rats were randomly divided into five groups: normal control group (given a normal feed diet and distilled water by gavage), NAFLD model (given HFD and distilled water by gavage), low-, medium-, and high-dose fermented hawthorn extract treatment groups (given HFD and different doses of fermented hawthorn extract by gavage). After 12 weeks of gavage administration, changes in body weight, liver/body weight ratio, serum liver enzymes, as well as triglyceride (TG) content and oxidative stress levels in rat liver tissueswere detected. Histological evaluation was performed to observe the degree of fat accumulation (steatosis). qRT-PCR and western blotting were performed to detect the mRNA and protein expression of cytochrome P4502E1 (CYP2E1, a key enzyme associated with lipid peroxidation), and lipogenic factors (sterol regulatory element-binding protein 1c (SREBP-1c) and fatty acid synthase (FAS)) in rat liver tissues. ResultsFermented hawthorn extract significantly reduced the body weight, decreased the levels of liver enzymes, improved hepatic steatosis, and exhibited obvious antioxidant effects. Fermented hawthorn extract also significantly down-regulated the mRNA and protein expression levels of CYP2E1, SREBP-1c and FAS. ConclusionOur findings suggested that fermented hawthorn extract can markedly reduce body weight, ameliorate HFD-induced NAFLD in rats, and exhibits significant antioxidant effects. Its underlying mechanism may depend on the inhibition of CYP2E1, SREBP-1c, and FAS expression.

Chitosan-Stabilized Selenium Nanoparticles Alleviate High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease (NAFLD) by Modulating the Gut Barrier Function and Microbiota.

Low molecular weight chitosan selenium nanoparticles (LCS-SeNPs), a biologically active compound derived from selenium polysaccharides, have demonstrated potential in addressing obesity. However, the mechanism through which LCS-SeNPs alleviate high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) remains unclear. Our results elucidated that LCS-SeNPs significantly inhibited fat accumulation and markedly improved the intestinal barrier by increasing mucus secretion from goblet cells. Moreover, LCS-SeNPs reshaped intestinal flora composition by increasing the abundance of mucus-associated microbiota (Bifidobacterium, Akkermansia, and Muribaculaceae_unclassified) and decreasing the abundance of obesity-contributed bacterium (Anaerotruncus, Lachnoclostridium, and Proteus). The modulation of intestinal microbiota by LCS-SeNPs influenced several metabolic pathways, including bile acid secretion, purine metabolites, and tryptophan derivation. Meanwhile, glycocholic acid and tauro-beta-muricholic acid were significantly reduced in the LCS-SeNP group. Our study suggests the crucial role of intestinal microbiota composition and metabolism, providing a new theoretical foundation for utilizing selenium polysaccharides in the intervention of HFD-induced NAFLD.

Effect of Ilex hainanensis Merr. On HFD-induced nonalcoholic fatty liver disease and rebalance of gut microbiota and bile acids metabolism in mice

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by excessive intracellular fat deposition in the hepatocytes, and the development is exacerbated by gut microbiota and bile acids metabolism disorders. Ilex hainanensis Merr. is a traditional medicine of the Zhuang nationality, historically esteemed for its efficacy in lowering blood pressure and lipid levels. This study aimed to investigate the pharmacodynamic effects in NAFLD mice and impacts on gut microbiota and bile acids (BAs) metabolism of I. hainanensis extract (IHA). 16 compounds were identified from IHA by HPLC-DAD-MS analysis. IHA significantly reduced body weight indexs, alanine transaminase (ALT) and aspartate transaminase (AST) activities, improved dyslipidemia and insulin resistance (IR), and effectively ameliorated hepatic steatosis in HFD-induced NAFLD mice. IHA also altered gut microbiota composition, particularly enhancing the abundance of bacteria involved in BAs metabolism, as well as augmented BAs synthesis in the liver and increased fecal excretion. In conclusion, our findings suggest that IHA holds promise in improving NAFLD conditions and modulating gut microbiota and BAs metabolism. These insights contribute to a deeper understanding of the mechanisms underlying IHA-mediated alleviation of lipid accumulation in NAFLD.

Chiglitazar attenuates high-fat diet-induced nonalcoholic fatty liver disease by modulating multiple pathways in mice

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide; however, effective intervention strategies for NAFLD are still unavailable. The present study sought to investigate the efficacy of chiglitazar, a pan-PPAR agonist, in protecting against NAFLD in mice and its underlying molecular mechanism. Male C57BL/6 J mice were fed a high-fat diet (HFD) for 8 weeks to generate NAFLD and the HFD was continued for an additional 10 weeks in the absence or presence of 5 mg/kg/d or 10 mg/kg/d chiglitazar by gavage. Chiglitazar significantly improved dyslipidemia and insulin resistance, ameliorated hepatic steatosis and reduced liver inflammation and oxidative stress in NAFLD mice. RNA-seq revealed that chiglitazar alleviated HFD-induced NAFLD in mice through multiple pathways, including fatty acid metabolism regulation, insulin signaling pathway, and AMPK signaling pathway. This study demonstrated the potential therapeutic effect of chiglitazar on NAFLD. Chiglitazar ameliorated NAFLD by modulating multiple pathways.

Identification of BAF60b as a Chromatin-Remodeling Checkpoint of Diet-Induced Fatty Liver Disease.

Overnutrition has gradually become the primary causative factor of nonalcoholic fatty liver disease (NAFLD). However, how nutritional signals are integrated to orchestrate the transcriptional programs important for NAFLD progression remains poorly understood. Here, we identified hepatic BAF60b as a lipid-sensitive subunit of the switch/sucrose-nonfermentable (SWI/SNF) chromatin-remodeling complex and is negatively associated with liver steatosis in mice and humans. Hepatic BAF60b deficiency promotes high-fat diet (HFD)-induced liver steatosis in mice, while transgenic expression of BAF60b in the liver attenuates HFD-induced obesity and NAFLD, both accompanied by a marked regulation of PPARγ expression. Mechanistically, through motif analysis of liver ATAC-Seq and multiple validation experiments, we identified CCAAT/enhancer-binding protein β (C/EBPβ) as the transcription factor that interacts with BAF60b to suppress PPARγ gene expression, thereby controlling hepatic lipid accumulation and NAFLD progression. This work uncovers hepatic BAF60b as a negative regulator of liver steatosis through C/EBPβ dependent chromatin remodeling.

Pea Albumin Extracted from Pea (Pisum sativum L.) Seeds Ameliorates High-Fat-Diet-Induced Non-Alcoholic Fatty Liver Disease by Regulating Lipogenesis and Lipolysis Pathways.

Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent liver disease globally. Pea albumin (PA) has demonstrated positive impacts on reducing obesity and improving glucose metabolism. In this research, a mouse model of NAFLD induced by a high-fat diet (HFD) was employed to examine the impact of PA on NAFLD and explore its potential mechanisms. The findings revealed that mice subjected to a HFD developed pronounced fatty liver alterations. The intervention with PA significantly lowered serum TC by 26.81%, TG by 43.55%, and LDL-C by 57.79%. It also elevated HDL-C levels by 1.2 fold and reduced serum ALT by 37.94% and AST by 31.21% in mice fed a HFD. These changes contributed to the reduction in hepatic steatosis and lipid accumulation. Additionally, PA improved insulin resistance and inhibited hepatic oxidative stress and inflammatory responses. Mechanistic studies revealed that PA alleviated lipid accumulation in HFD-induced NAFLD by activating the phosphorylation of AMPKα and ACC, inhibiting the expression of SREBF1 and FASN to reduce hepatic lipogenesis, and increasing the expression of ATGL, PPARα, and PPARγ to promote lipolysis and fatty acid oxidation. These results indicate that PA could serve as a dietary supplement for alleviating NAFLD, offering a theoretical foundation for the rational intake of PA in NAFLD intervention.

Integrated transcriptome and metabolome study reveal the therapeutic effects of nicotinamide riboside and nicotinamide mononucleotide on nonalcoholic fatty liver disease

Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However, few studies have focused on their role in ameliorating hepatic metabolic disturbances. In the present study, the effects of NMN and NR on the liver of mice with nonalcoholic fatty liver disease (NAFLD) were investigated via transcriptome and metabolome analyses. NMN and NR reduced body weight gain, improved glucose homeostasis, regulated plasma lipid levels, and ameliorated liver injury, oxidative stress, and lipid accumulation in mice with HFD-induced NAFLD. Integrated transcriptome and metabolome analyses indicated that NMN and NR altered the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and linoleic acid metabolism pathways, increased saturated fatty acid (palmitic acid, stearate, and arachidic acid) content, and increased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content. Quantitative reverse transcription PCR (qRT-PCR) showed that NMN and NR primarily promoted arachidonic acid and linoleic acid catabolism via cytochrome P450 (CYP450) enzymes. This study established a theoretical foundation for the potential use of NMN and NR in future clinical settings.

Smilax china L. polysaccharide prevents HFD induced-NAFLD by regulating hepatic fat metabolism and gut microbiota

BackgroundThe increasing incidence of nonalcoholic fatty liver disease(NAFLD) has urged the development of new therapeutics. NAFLD is intimately linked to gut microbiota due to the hepatic portal system, and utilizing natural polysaccharides as prebiotics has become a prospective strategy for preventing NAFLD. Smilax china L. polysaccharide (SCP) possesses excellent hepatoprotective and anti-inflammatory activity. However, its protective effects on NAFLD remains unclear. PurposeThe goal of this study was to explore the protective effects of SCP on high-fat diet (HFD)-induced NAFLD mice by regulating hepatic fat metabolism and gut microbiota. MethodsExtraction and isolation from Smilax china L. rhizome to obtain SCP. C57BL/6J mice were distributed to six groups: Control (normal chow diet), HFD-fed mice were assigned to HFD, simvastatin (SVT), and low-, medium-, high-doses of SCP for 12 weeks. The body, liver, and different adipose tissues weights were detected, and lipids in serum and liver were assessed. RT-PCR and Western blot were used to detect the hepatic fat metabolism-related genes and proteins. Gut microbiota of cecum contents was profiled through 16S rRNA gene sequencing. ResultsSCP effectively reversed HFD-induced increase weights of body, liver, and different adipose tissues. Lipid levels of serum and liver were also significantly reduced after SCP intervention. According to the results of RT-PCR and western blot analysis, SCP treatment up-regulated the genes and proteins related to lipolysis were up-regulated, while lipogenesis-related genes and proteins were down-regulated. Furthermore, the HFD-induced dysbiosis of intestinal microbiota was similarly repaired by SCP intervention, including enriching beneficial bacteria and depleting harmful bacteria. ConclusionSCP could effectively prevent HFD-induced NAFLD, might be considered as a prebiotic agent due to its excellent effects on altering hepatic fat metabolism and maintaining gut microbiota homeostasis.

Effects of triglyceride and ethyl ester forms of EPA on hepatic lipid metabolism in mice with non-alcoholic fatty liver disease

In this study, the beneficial effects of EPA in ethyl esters (EE) and triacylglycerides (TAG) forms on high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) were studied and compared. Results indicated that both EPA-TAG and EPA-EE can alleviate pathological features of NAFLD, such as hepatic lipid accumulation and lobular inflammation, with a more pronounced protective effects observed in EPA-TAG treated mice. The integrated hepatic transcriptomic, metabolic and gut microbiota profiles suggest that EPA-TAG and EPA-EE improved hepatic steatosis by suppression of food intake and lipogenesis, promotion of lipid and phospholipid PUFA remodeling, ketogenesis and fatty acids oxidation, possibly via activating the AMPK/adipocytokine signaling pathway. The protective effect of EPA was also associated with the regulation of intestinal flora structure. In general, EPA-TAG was found to be more effective than EPA-EE in preventing HFD-induced NAFLD by reducing appetite, improving hepatic lipid metabolism, increasing energy expenditure, and enhancing gut-liver cross-talk.

Dual-Stimuli-Responsive Gut Microbiota-Targeting Nitidine Chloride-CS/PT-NPs Improved Metabolic Status in NAFLD.

Nitidine chloride (NC) is a botanical drug renowned for its potent anti-inflammatory, antimalarial, and hepatocellular carcinoma-inhibiting properties; however, its limited solubility poses challenges to its development and application. To address this issue, we have devised a colon-targeted delivery system (NC-CS/PT-NPs) aimed at modulating the dysbiosis of the gut microbiota by augmenting the interaction between NC and the intestinal microbiota, thereby exerting an effect against nonalcoholic fatty liver disease. The NC-CS/PT-NPs were synthesized using the ion gel method. Subsequently, the particle size distribution, morphology, drug loading efficiency, and release behavior of the NC-CS/PT-NPs were characterized. Furthermore, the impact of NC-CS/PT-NPs on non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD) in mice was investigated through serum biochemical analysis, ELISA, and histochemical staining. Additionally, the influence of NC-CS/PT-NPs on intestinal microbiota was analyzed using 16S rDNA gene sequencing. The nanoparticles prepared in this study have an average particle size of (255.9±5.10) nm, with an encapsulation rate of (72.83±2.13) % and a drug loading of (4.65±0.44) %. In vitro release experiments demonstrated that the cumulative release rate in the stomach and small intestine was lower than 22.0%, while it reached 66.75% in the colon. In vivo experiments conducted on HFD-induced NAFLD mice showed that treatment with NC-CS/PT-NPs inhibited weight gain, decreased serum aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and lipid levels, improved liver and intestinal inflammation, and altered the diversity of gut microbiota in mice. This study provides new evidence for the treatment of NAFLD through the regulation of gut microbiota using active ingredients from traditional Chinese medicine.

Taurine Regulates the Expression of Interleukin -17/10 and Intestinal Flora and Protects the Liver and Intestinal Mucosa in a Nonalcoholic Fatty Liver Disease Rat Model.

To investigate the intestinal inflammatory response and the abundance of intestinal bacteria in rats with high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) and assess the intervention effects of taurine (TAU). Forty male Sprague-Dawley rats were randomly divided into five groups: group I, normal diet and normal saline gavage; group II, normal diet and TAU gavage; group III, HFD and normal saline gavage; group IV, HFD and TAU gavage (from the 1st week); group V, HFD and TAU gavage (from the 10th week). At the end of the 16th week, all the animals were sacrificed. Body weight, liver weight, liver function, and serum lipid levels were measured. The histopathologies of the liver and ileum were observed. The mRNA and protein expression levels of interleukin 17 (IL-17) and IL-10 in the ileum were detected by reverse transcription quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Three types of bacteria were detected in intestinal feces using the 16S rDNA qPCR method. The ileal IL-17 level in group III was significantly higher than those in the other four groups (P < 0.01). The ileal IL-10 mRNA levels in group IV was significantly higher than those in groups III and V (P < 0.05), and IL-10 protein MOD levels in group III was significantly lower than those in the other four groups (P < 0.01). The numbers of Lactobacillus in group III were significantly lower than those in the other four groups (P < 0.01 or P < 0.05). The numbers of Bifidobacteria in groups IV and V were significantly increased compared with that in group III (P < 0.05). TAU may down-regulate the expression of IL-17, up-regulate the expression of IL-10 and regulate the intestinal flora, and alleviate the liver and intestinal damage in rats with HFD-induced NAFLD.

Hugan Qingzhi tablets attenuates endoplasmic reticulum stress in nonalcoholic fatty liver disease rats by regulating PERK and ATF6 pathways

BackgroundEndoplasmic reticulum (ER) stress, promoting lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Hugan Qingzhi tablets (HQT) has a definite effect in the clinical treatment of NAFLD patients, but its mechanism is still unclear. This study aims to investigate the effects of HQT on ER stress in the liver tissues of NAFLD rats and explore the underlying mechanism.MethodsThe NAFLD rat model was managed with high-fat diet (HFD) for 12weeks. HQT was administrated in a daily basis to the HFD groups. Biochemical markers, pro-inflammatory cytokines, liver histology were assayed to evaluate HQT effects in HFD-induced NAFLD rats. Furthermore, the expression of ER stress-related signal molecules including glucose regulating protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), p-PERK, eukaryotic translation initiation factor 2α (EIF2α), p-EIF2α, activating transcription factor 4 (ATF4), acetyl-coenzyme A-carboxylase (ACC), activating transcription factor (ATF6), and nuclear factor-kappa B-p65 (NF-κB-p65) were detected by western blot and/or qRT-PCR.ResultsThe histopathological characteristics and biochemical data indicated that HQT exhibited protective effects on HFD-induced NAFLD rats. Furthermore, it caused significant reduction in the expression of ERS markers, such as GRP78, PERK, p-PERK, and ATF6, and subsequently downregulated the expression of EIF2α, p-EIF2α ATF4, ACC, and NF-κB-p65.ConclusionsThe results suggested that HQT has protective effect against hepatic steatosis and inflammation in NAFLD rats by attenuating ER stress, and the potential mechanism is through inhibition of PERK and ATF6 pathways.

Comparison of the anti-inflammatory and antilipidemic activity of diosmin and saroglitazar in a model of nonalcoholic fatty liver induced by a high-fat diet in Wistar rats.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver-related metabolic disorder in the world, with a global prevalence of 25%. Compounds with anti-inflammatory, lipid-lowering, and insulin-sensitizing properties can be used for the prevention or treatment of NAFLD. Therefore, this study was conducted to investigate the effect of saroglitazar (a dual PPARα/γ agonist) and diosmin (a flavonoid) on non-alcoholic fatty liver induced by a high-fat diet (HFD) in Wistar rats. Forty male Wistar rats (6-8 weeks old) were fed an HFD to induce NAFLD. After 7 weeks, rats were divided into four groups: group1 was fed HFD, and the other groups received HFD+saroglitazar, HFD+diosmin, and HFD+ saroglitazar+diosmin. We examined body and liver weight, histopathology, serum levels of liver enzymes (ALT and AST), and lipid profiles (LDL-C and HDL-C) using the standard protocols. qRT-PCR was also used to examine the expression of PPARα, PPARγ, SREBP1c, FAS, ACC, CPT1α, and pro-inflammatory genes (IL6, TNFα, and TGFβ). Rats fed the HFD showed characteristics of NAFLD (pathologically and biochemically). Administration of saroglitazar and diosmin alone caused a significant decrease in the levels of PPARγ, SREBP1c, FAS, ACC, ALT, AST, LDL-C, and pro-inflammatory genes and a significant increase in PPARα, CPT1a, and HDL-C in comparison with the HF group (P<0.05). Their combined effect was more evident. Our results showed that diosmin, like saroglitazar, significantly ameliorated inflammatory and lipid profiles in HFD-induced NAFLD, suggesting that diosmin, as a natural compound, could be a suitable alternative to saroglitazar.

Vagal Stimulation Ameliorates Non-Alcoholic Fatty Liver Disease in Rats.

The harmful consequences of non-alcoholic fatty liver disease (NAFLD) are posing an increasing threat to public health as the incidence of diabetes and obesity increases globally. A non-invasive treatment with a range of autonomic and metabolic benefits is transcutaneous vagus nerve stimulation (tVNS). To investigate the possible preventive impacts of VNS against adult rats' NAFLD caused by a high-fat diet (HFD) and to clarify the underlying mechanisms. A total of thirty-two adult male rats were split into two groups: the HFD-induced NAFLD group (n = 24) and the control normal group (n = 8). The obesogenic diet was maintained for 12 weeks to induce hepatic steatosis. The HFD-induced NAFLD group (n = 24) was separated into three groups: the group without treatment (n = 8), the group with sham stimulation (n = 8), and the group with VNS treatment (n = 8). VNS was delivered for 30 min per day for 6 weeks after the establishment of NAFLD using a digital TENS device. The subsequent assessments included hepatic triglyceride, cholesterol content, serum lipid profile, and liver function testing. In this context, inflammatory biomarkers (TNF-α, IL-6) and hepatic oxidative stress (MDA, SOD, and GPx) were also assessed. To clarify the possible mechanisms behind the protective benefits of VNS, additional histological inspection and immunohistochemistry analysis of TNF-α and Caspase-3 were performed. In the NAFLD-affected obese rats, VNS markedly decreased the rats' body mass index (BMI) and abdominal circumference (AC). Liver function markers (albumin, ALT, and AST) and the serum lipid profile-which included a notable decrease in the amounts of hepatic triglycerides and cholesterol-were both markedly improved. Additionally, oxidative stress and inflammatory indicators showed a considerable decline with VNS. Notably, the liver tissues examined by histopathologists revealed that there is evidence of the protective impact of VNS on the oxidative and inflammatory states linked to HFD-induced NAFLD while maintaining the architectural and functional condition of the liver. Our findings suggest that VNS may represent a promising therapeutic candidate for managing NAFLD induced by obesity. It can be considered to be an effective adjuvant physiological intervention for the obese population with NAFLD to spare the liver against obesity-induced deleterious injury.