High-fat Diet-induced Non-alcoholic Fatty Liver Research Articles

Swertia mussotii prevents high-fat diet-induced non-alcoholic fatty liver disease in rats by inhibiting expression the TLR4/MyD88 and the phosphorylation of NF-κB

Context Swertia mussotii Franch. (Gentianaceae) is a source of the traditional Tibetan medicine, ZangYinChen, and is used to treat chronic hepatitis and many types of jaundice. Objective This study explored the therapeutic effects and mechanism of S. mussotii on non-alcoholic fatty liver disease in diet-induced hypercholesterolaemia. Materials and methods After a week of adaptive feeding, 32 Sprague-Dawley rats were divided into four groups: (1) Control, (2) Control-S, (3) Model, and (4) Model-S. During the 12 experimental weeks, we established the Model using a high-fat diet. Control-S and Model-S were given 1.0 g/kg S. mussotii water extract via gavage starting in the fifth week until the end of experiment. Results When compared with Model rats, the S. mussotii water extract led to a reduction in high-density lipoproteins (43.9%) and albumin (13.9%) and a decrease in total cholesterol (54.0%), triglyceride (45.6%), low-density lipoproteins (8.6%), aspartate aminotransferase (11.0%), alanine aminotransferase (15.5%), alkaline phosphatase (19.1%), total protein (6.4%), and glucose (20.8%) in serum. A reduction in three cytokines (IL-1β, IL-6, and TNFα) was detected. Histopathological examination showed that liver steatosis was significantly relieved in S. mussotii-treated high-fat diet rats. S. mussotii also caused a downregulation in the expression of TLR4 (43.2%), MyD88 (33.3%), and a decrease in phosphorylation of NF-κB. Discussion and conclusions Our findings indicate that S. mussotii may act as a potential anti-inflammation drug via inhibition of the TLR4/MyD88/NF-κB pathway. Further in vivo and in vitro studies are needed to validate its potential in clinical medicine.

Oudemansiella raphanipies Polysaccharides Improve Lipid Metabolism Disorders in Murine High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease.

Oudemansiella raphanipies, also called “Edible Queen,” is a mushroom that possesses antioxidant, anti-inflammatory, anti-bacterial, anti-tumor and immunity-enhancing properties. The present study aimed to assess the effect of O. raphanipies-derived polysaccharide (ORPS) on the progression of nonalcoholic fatty liver disease (NAFLD) in mice. We studied the structure of ORPS-1 by high-performance gel permeation chromatography (HPGPC), ion chromatography-mass spectrometry (GC-MS), and Fourier transform-infrared spectroscopy (FT-IR). ORPS-1 mainly comprised galactose, fucose, glucose, mannose, and xylose, following an 18:6:6:4:1 molar ratio. In addition, the therapeutic effect as well as a potential mechanism of ORPS-1 in the treatment of high-fat diet (HFD)-induced NAFLD were investigated. The results showed that ORPS-1 improved liver function, ameliorated liver steatosis, and reduced lipid droplet accumulation in HFD mice. A metabolomics approach with GC-MS was utilized to evaluate liver improvement by ORPS-1 treatment. Principal component analysis showed that liver metabolic profiling was significantly altered by HFD feeding or treatment with an intermediate dose of ORPS-1 in mice compared with that of control mice. By investigating the metabolic pathways with identified biomarkers, various pathways such as steroid biosynthesis, valine, leucine, and isoleucine biosynthesis, glycerol phospholipid metabolism, glyceride metabolism, and arginine and proline metabolism in HFD mice were observed to be significantly influenced by ORPS-1 treatment. The results indicate ORPS-1 metabolic effects on liver tissues, provide methods for assessing the molecular impact of ORPS-1 on NAFLD, and suggest the potential mechanism underlying its health benefits.

RNA adenosine deaminase (ADAR1) alleviates high-fat diet-induced nonalcoholic fatty liver disease by inhibiting NLRP3 inflammasome

AbstractNonalcoholic fatty liver disease (NAFLD) is a chronic inflammatory disease in which nucleotide-binding domain of leucine-rich repeat protein 3 (NLRP3) inflammasome plays an important role. The present research was aimed to explore the protective function of ADAR1, an RNA editing enzyme, against inflammatory damages in high-fat diet (HFD)-induced NAFLD through inhibiting NLRP3 inflammasome and subsequent inflammation. A total of 30 patients with NAFLD were investigated, and ADAR1 mRNA expression in peripheral blood monocytes surveyed. The in vivo study used lentivirus to explore the function of ADAR1 overexpression in the HFD-induced mouse model of NAFLD. The in vitro study used lentivirus and siRNA to explore the function of ADAR1 on the NLRP3 inflammasome activation in THP-1 cells. Results shown that the ADAR1 expression was upregulated in NAFLD patients in comparison to healthy controls. In vivo, the upregulation of ADAR1 impaired NLRP3 inflammasome activation and alleviated liver disease in HFD mice in comparison to the control group. Moreover, ADAR1 overexpression attenuated NLRP3 inflammasome in lipopolysaccharide (LPS)+ palmitic acid (PA)-induced THP-1 cells, while ADAR1 knockdown increased the NLRP3 inflammasome activation. Furthermore, we speculated that c-Jun may participate in ADAR1's inhibition of NLRP3 inflammasome. Our results suggested that ADAR1 is a potential treatment target for NAFLD via regulating the activation of NLRP3 inflammasome.

Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. Combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD.

Effect of aqueous extract of Colocasia esculenta against high-fat diet-induced non-alcoholic fatty liver disease in rats

Non-alcoholic fatty liver disease (NAFLD) is becoming a major public health problem due to the increasing incidence of obesity and diabetes in India for the last two decades. The present work is aimed to investigate the effect of aqueous extract of Colocasia esculenta against (AECE) high-fat diet-induced non-alcoholic fatty liver disease in Wistar albino rats. Wistar albino rats were assigned in to four groups as follows; Group I: Normal conventional diet, Group II: High fat diet, Group III & Group IV: Combined high fat diet and different doses of Colocasia esculenta (200 and 400 mg/kg, p.o) for 4 weeks.Treatment with aqueous extract of Colocasia esculenta(200mg/kg, 400mg/kg bw) significantly reduced the body weight and weight gain. In addition, it also significantly reduced the serum triglycerides, total cholesterol, LDL cholesterol, VLDL cholesterol and showed a significant increase in HDL cholesterol as well as significant improvement in liver cholesterol and triglyceride content. AECE treated rats exhibited a significant beneficial effects on levels of liver function markers and oxidative stress and also reversed the histopathological changes.The study suggested the therapeutic potential of AECE against NAFLD, acting in part through anti-obesity, antioxidant mechanisms, and liver marker enzymes.

Yogurt-derived Lactobacillus plantarum Q16 alleviated high-fat diet-induced non-alcoholic fatty liver disease in mice

Accumulating evidence revealed that some probiotics regulated lipid metabolism and alleviated diet-induced non-alcoholic fatty liver disease (NAFLD). This study mainly explored whether yogurt-derived Lactobacillus plantarum Q16 modulated lipid and energy metabolism, and suppressed microbial dysbiosis in high-fat diet (HFD)-fed mice. Results showed that oral administration of L. plantarum Q16 improved serum and hepatic lipid profile. Protein analysis showed that L. plantarum Q16 could reduce hepatic lipid content by reducing the expression of FAS, ACC, SCD-1, Srebp-1c and ATGL, but increasing expression levels of CPT-1α, PPAR-α and ATGL. Meanwhile, L. plantarum Q16 also improved hepatic energy metabolism by regulating FGF21/adiponectin/AMPKα/PGC-1α signaling pathway. Metagenomic analysis also discovered that L. plantarum Q16 increased species diversity and richness of intestinal microbiota, promoted proliferation of beneficial commensals and suppressed the growth of endotoxin-producing microorganisms in the colon of HFD-fed mice. Overall, L. plantarum Q16 protected against HFD-induced NAFLD by improving hepatic profile and regulating colonic microbiota composition.

PREX1 depletion ameliorates high-fat diet-induced non-alcoholic fatty liver disease in mice and mitigates palmitic acid-induced hepatocellular injury via suppressing the NF-κB signaling pathway

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases worldwide. Oxidative stress has been considered a key factor in the pathogenesis of NAFLD. Phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger 1 (PREX1), a guanine nucleotide exchange factor for Rac, has been associated with inflammation and oxidative stress. This study aimed to investigate the biological function of PREX1 in the progression of NAFLD. Male C57BL/6 mice were fed a high-fat diet for 12 weeks to induce NAFLD in vivo. Adeno-associated virus type 8-mediated liver-specific PREX1 depletion was employed to investigate the role of PREX1 in the progression of high-fat diet-induced NAFLD. Murine hepatocyte cell line AML-12 was stimulated with palmitic acid for 24 h to induce steatosis in vitro. PREX1 depletion was carried out by transfection with PREX1 small interfering RNA. Results showed that PREX1 depletion exerted protective effects against lipid accumulation, oxidative stress and inflammation and inhibited activation of the nuclear factor-κB (NF-κB) signaling pathway in vivo and in vitro. Subsequently, NF-κB inhibitor BAY11–7082 was applied to investigate the role of the NF-κB signaling pathway in the protective effect of PREX1 inhibition against NAFLD. We confirmed that PREX1 inhibition mitigated palmitic acid-induced hepatocellular inflammation mainly via the NF-κB signaling pathway and lipid accumulation and oxidative stress at least partly via the NF-κB signaling pathway. This study highlights the biological function of PREX1 in the pathogenesis of NAFLD.

Ramulus Mori (Sangzhi) Alkaloids Alleviate High-Fat Diet-Induced Obesity and Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes mellitus (T2DM) have highly related mechanisms. Ramulus Mori (Sangzhi) alkaloids (SZ-A) from Morus alba L. were approved in 2020 for the treatment of T2DM. In this study, we examined the therapeutic effects and mechanism of SZ-A on obesity and NAFLD in mice. Mice (C57BL/6J) fed a high-fat diet (HFD) for 14 weeks were treated with SZ-A for another 6 weeks. HFD-induced weight gain was reduced by SZ-A in a dose-dependent manner. SZ-A treatment significantly stimulated adiponectin expression and secretion in adipose tissue and 3T3-L1 adipocytes. Additionally, SZ-A markedly reduced hepatic steatosis (triglyceride, total cholesterol) and expression of pro-inflammatory and pro-fibrotic genes. SZ-A regulated lipid metabolism and oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH)) in the liver. Palmitic acid-induced insulin resistance and lipid accumulation in HepG2 cells were also repressed by SZ-A. Collectively, SZ-A protected mice from HFD-induced NAFLD through an indirect effect of improved systemic metabolism reducing bodyweight, and a direct effect by enhancing the lipid metabolism of HepG2 cells. The weight-loss effect of SZ-A in mice was partly due to improved fatty oxidation instead of influencing food consumption.

Potential Protective Effect of Zingiber officinale in Comparison to Rosuvastatin on High-fat diet-induced Non-alcoholic Fatty Liver Disease in Rats

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease affecting nearly 25% of adults worldwide with related risk factors including obesity, metabolic, and inflammatory diseases. Many therapeutic remedies of natural or synthetic properties were used. AIM: This study aimed to investigate and compare the effects of ginger/rosuvastatin (ROSU) on the liver of rats with induced NAFLD. MATERIALS AND METHODS: Forty adult male albino rats were used in this study and divided into four equal subgroups, Group I, control received the standard rat chow diet and given normal saline (1 ml/kg/day), Group II, high-fat diet (HFD) group, Group III, received HFD+ ROSU (15 mg/kg/day), and Group IV, HFD+ Zingiber officinale (10% W/V) for 6 weeks. At the end of our experiment, the rats were sacrificed then blood samples were collected for biochemical analysis of lipid profiles and liver enzymes, liver specimen was prepared for light and electron microscopic examination, and measurement of tissue level of malondialdehyde. RESULTS: NAFLD caused degenerative changes and lipid deposition in liver cells as evidenced by microscopic results and laboratory tests. Treatment with ginger/ROSU alleviated those changes. CONCLUSION: Ginger and ROSU could ameliorate liver functions in NAFLD and ginger effect is superior to ROSU.

Chicory polysaccharides alleviate high-fat diet-induced non-alcoholic fatty liver disease via alteration of lipid metabolism- and inflammation-related gene expression

Administration of chicory polysaccharides (CP) can modify lipid metabolism, improve dyslipidemia, and reduce liver inflammation, all of which may help alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain unclear. This study aimed to gain further understanding of the potential molecular mechanisms that mediate the protective effects of CP against NAFLD via transcriptomic and metabolomic analyses. Hepatic RNA-sequencing analysis demonstrated that long-term intake of CP restored expression of lipid metabolism-related genes Xbp1, Insig2, and Cth in NAFLD rats, thereby inhibiting de novo lipogenesis. Moreover, CP consumption restored expression levels of genes involved in pro-inflammatory responses, such as Irf1. In addition, metabolic data confirmed that CP treatment increased levels of L-palmitoylcarnitine and hexadecanoyl-CoA, implying that CP administration can promote hepatic fatty acid β-oxidation. The present results demonstrate the underlying mechanisms of CP in high-fat diet-induced NAFLD rats and suggest that CP treatment might provide a dietary therapeutic tool for the treatment of NAFLD in humans.

Tectorigenin ameliorated high-fat diet-induced nonalcoholic fatty liver disease through anti-inflammation and modulating gut microbiota in mice

Nonalcoholic fatty liver disease (NAFLD) is a complex pathogenesis of liver disease combined with liver inflammation and gut microbiota dysbiosis. Tectorigenin (Tg) is derived from many plants with excellent anti-inflammation activity. However, the beneficial effect of Tg on NAFLD associated with gut microbiota remained unclear. This study aimed to investigate the underlying beneficial effect of Tg on NAFLD in high-fat diet (HFD)-fed mice. Results showed that Tg alleviated lipid profiles and liver steatosis, and reduced serum lipopolysaccharide (LPS) and total bile acid (TBA) levels. Besides, RT-qPCR and Western blot suggested that Tg alleviated hepatic lipid accumulation through inhibiting the lipogenesis and promoting the lipolysis, prevented gut-derived LPS-induced liver inflammatory via restoring intestinal barrier and restraining pro-inflammatory cytokines release, meanwhile, promoted the BA circulation via activating BA receptor and promoting BA synthesis. Moreover, Tg reverted the HFD-induced gut microbial dysbiosis by promoting the growth of beneficial Akkermansia, and inhibiting the proportions of harmful microbes, including Blautia, Lachnoclostridium, Lachnospiraceae_UCG-006, Roseburia, Romboutsia and Faecalibaculum, which were highly correlated with NAFLD-related parameters in serum and liver. Thus, Tg could attenuate NAFLD through mediating the liver-gut axis, and it could be used as a dietary supplement for NAFLD treatment via its anti-inflammatory and prebiotic effects.

Er-Chen Decoction Alleviates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Rats through Remodeling Gut Microbiota and Regulating the Serum Metabolism.

Many studies have found that the dysfunction in gut microbiota and the metabolic dysfunction can promote nonalcoholic fatty liver disease (NAFLD) development. Er-Chen decoction (EC) can be used in the treatment of NAFLD. However, the mechanism of this hepatoprotection is still unknown. In this study, we constructed a rat model with NAFLD fed with high-fat chow and administered EC treatment. The therapeutic effects of EC on NAFLD were evaluated by measuring transaminases, blood lipid levels, and pathological changes in the liver. In addition, we measured the effects of EC on liver inflammatory response and oxidative stress. The changes in gut microbiota after EC treatment were studied using 16S rRNA sequencing. Serum untargeted metabolomics analysis was also used to study the metabolic regulatory mechanisms of EC on NAFLD. The results showed that EC decreased the serum transaminases and lipid levels and improved the pathological changes in NAFLD rats. Furthermore, EC enhanced the activities of SOD and GSH-Px and decreased MDA level in the liver. EC treatment also decreased the gene and protein levels of IL-6, IL-1β, and TNF-α in the liver and serum. The 16S rRNA sequencing and untargeted metabolomics indicated that EC treatment affected the gut microbiota and regulated serum metabolism. Correlation analysis showed that the effects of EC on taurine and hypotaurine metabolism, cysteine and methionine metabolism, and vitamin B6 metabolism pathways were associated with affecting in the abundance of Lactobacillus, Dubosiella, Lachnospiraceae, Desulfovibri, Romboutsia, Akkermansia, Intestinimonas, and Candidatus_saccharimonas in the gut. In conclusion, our study confirmed the protective effect of EC on NAFLD. EC could treat NAFLD by inhibiting oxidative stress, reducing inflammatory responses, and improving the dysbiosis of gut microbiota and the modulation of the taurine and hypotaurine metabolism, cysteine and methionine metabolism, and vitamin B6 metabolism pathways in serum.

Pharmacological systemic analysis of gardenia fructus against non-alcoholic fatty liver disease and validation of animal models.

[Purpose]We aimed to investigate the systemic pharmacological analysis of gardenia fructus (GF) and the proof of concepts. We examined the antioxidant and anti-inflammatory effects in high-fat (HF) diet mice.[Methods]The active compounds of GF and the target genes were identified using the Traditional Chinese Medicine Database and Analysis Platform (oral bioavailability ≥ 30%, Caco-2 permeability ≥ -0.4, and drug-likeness ≥ 0.18). The rats were divided into four groups: untreated group, HF group, HF and metformin (17 mg/kg) treated group, and HF and treated with GF (28 mg/kg) for 8 weeks group. Hepatic lesion changes and markers were analyzed using hematoxylin and eosin staining and immunohistochemistry assay.[Results]In the systemic analysis, we identified 14 active compounds including A, B, and C. From these 14 compounds, 242 biological target genes were identified. The top 10 Gene Ontology were analyzed using GO-biological process analysis: removal of superoxide radicals, regulation of endothelial cell apoptotic process, and cellular response to lipopolysaccharide. GF extracts in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mice models significantly regulated hepatic lesion markers, such as mTOR, 8-Hydroxy-2'-deoxyguanosine as well as oxidative stress activities, TGF-β, and phosphorylation of ERK1/2.[Conclusion]These results suggest that GF, as an exercise supplement, can alleviate NAFLD disease or fatty liver inflammation. Further studies are required to verify the synergistic effect of GF treatment combined with exercise, which is known to alleviate NAFLD and fatty liver inflammation.

Whole Body Ip6k1 Deletion Protects Mice from Age-Induced Weight Gain, Insulin Resistance and Metabolic Dysfunction.

(1) Background: We previously demonstrated that disruption of IP6K1 improves metabolism, protecting mice from high-fat diet-induced obesity, insulin resistance, and non-alcoholic fatty liver disease and steatohepatitis. Age-induced metabolic dysfunction is a major risk factor for metabolic diseases. The involvement of IP6K1 in this process is unknown. (2) Methods: Here, we compared body and fat mass, insulin sensitivity, energy expenditure and serum-, adipose tissue- and liver-metabolic parameters of chow-fed, aged, wild type (aWT) and whole body Ip6k1 knockout (aKO) mice. (3) Results: IP6K1 was upregulated in the adipose tissue and liver of aWT mice compared to young WT mice. Moreover, Ip6k1 deletion blocked age-induced increase in body- and fat-weight and insulin resistance in mice. aKO mice oxidized carbohydrates more efficiently. The knockouts displayed reduced levels of serum insulin, triglycerides, and non-esterified fatty acids. Ip6k1 deletion partly protected age-induced decline of the thermogenic uncoupling protein UCP1 in inguinal white adipose tissue. Targets inhibited by IP6K1 activity such as the insulin sensitivity- and energy expenditure-inducing protein kinases, protein kinase B (PKB/Akt) and AMP-activated protein kinase (AMPK), were activated in the adipose tissue and liver of aKO mice. (4) Conclusions: Ip6k1 deletion maintains healthy metabolism in aging and thus, targeting this kinase may delay the development of age-induced metabolic dysfunction.

Fenofibrate Improves Insulin Resistance and Hepatic Steatosis and Regulates the Let-7/SERCA2b Axis in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Mice.

Fenofibrate is widely used in clinical therapy to effectively ameliorate the development of non-alcoholic fatty liver disease (NAFLD); however, its specific molecular mechanism of action remains largely unknown. MicroRNAs (miRNAs) are key mediators in regulating endoplasmic reticulum (ER) stress during NAFLD, and the deregulation of miRNAs has been demonstrated in NAFLD pathophysiology. The present study aimed to identify whether fenofibrate could influence miRNA expression in NAFLD and investigate the specific mechanism of action of fenofibrate in lipid metabolism disorder-associated diseases. We found that fenofibrate alleviated ER stress and increased the levels of SERCA2b, which serves as a regulator of ER stress. Additionally, the levels of let-7 miRNA were regulated by fenofibrate; let-7 was found to target the 3′ untranslated region of SERCA2b. The present data suggest that the protective effects of fenofibrate against insulin resistance and its suppressive activity against excessive hepatic lipid accumulation may be related to the alteration of the let-7/SERCA2b axis and alleviation of ER stress.

Effect of diosmetin on young rats with high-fat diet-induced non-alcoholic fatty liver disease


 
 
 
 Purpose: To determine the effect of diosmetin on young, non-alcoholic fatty liver disease (NAFLD) rats.
 Methods: Five groups of SD rats were used: control group, high-fat diet group, low-dose diosmetin group, medium-dose diosmetin group, and high-dose diosmetin group, each with 10 rats. After 3 months, interleukin 6 (IL-6), IL-1β) and TNF-α) were assayed. Protein expressions of p-AMPKα, CPT-1 and PPAR-α, AMPKα, SREBP-1c and FAS were assayed.
 Results: In the high-fat diet group, the levels of p-AMPKα, CPT-1 and PPAR-α were lower than the corresponding control values, while p-AMPKα, CPT-1 and PPAR-α levels were dose-dependently higher in all diosmetin groups than in NAFLD group (p < 0.05). There were higher levels of SREBP-1c and FAS in the high-fat diet group than in control group, while SREBP-1c and FAS levels in all diosmetin groups were dose-dependently lower than the corresponding levels in NAFLD group. Serum IL-6, IL-1β and TNF-α levels in NAFLD group were raised, relative to control values (p < 0.05).
 Conclusion: Diosmetin alleviates NAFLD lesions induced by high-fat diet, slows down liver cell apoptosis, and inhibits inflammation via activation of AMPK pathway. Thus, diosmetin has potentials for use in the repair of hepatic damage induced by high-fat diet.
 
 
 

The combination of berberine and evodiamine ameliorates high-fat diet-induced non-alcoholic fatty liver disease associated with modulation of gut microbiota in rats.

Nonalcoholic fatty liver disease (NAFLD) is considered to be a manifestation of hepatic metabolic syndrome. Some studies on the pathogenesis of NAFLD by targeting gut microbiota have attracted wide attention. Previous studies have demonstrated the positive effects of berberine and evodiamine on metabolic diseases and gut microbiota dysbiosis. However, it is not known whether the combination of berberine and evodiamine (BE) can prevent the development of high-fat diet (HFD)-induced NAFLD. Therefore, we aimed to explore the protective effects of BE on the development of HFD-induced NAFLD from the perspective of the gut microbiota. Gut microbiota profiles were established by high throughput sequencing of the bacterial 16S ribosomal RNA gene. The effects of BE on liver and intestinal tissue, intestinal barrier integrity, and hepatic inflammation were also investigated. The results showed that the abundance and diversity of gut microbiota were enriched by BE treatment, with an increase in beneficial bacteria, such as Lactobacillus, Ruminococcus, and Prevotella, and a decrease in pathogenic bacteria such as Fusobacterium and Lachnospira. In addition, BE effectively improved liver fat accumulation and tissue damage, inhibited the apoptosis of intestinal epithelial cells, increased the contents of intestinal tight junction proteins, and decreased the expression of pro-inflammatory factors. Consequently, BE treatment could be an effective and alternative strategy for alleviating NAFLD by modulating gut microbiota and safeguarding the intestinal barrier.

DHA-enriched phosphatidylcholine from Clupea harengus roes regulates the gut-liver axis to ameliorate high-fat diet-induced non-alcoholic fatty liver disease.

In this study, the protective effect of DHA-enriched phosphatidylcholine (DHA-PC) from Clupea harengus roes against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) was investigated. Our results indicated that DHA-PC significantly decreased the murine body weights, liver indexes, serum ALT, AST, and LPS levels, improved the serum lipid levels (TG, TC, LDL-C, HDL-C, NEFA), relieved the hepatic levels of the pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), and hepatic oxidative stress (MDA, SOD, GSH-Px, and CAT) in mice fed on HFD. DHA-PC significantly decreased protein expression levels of TLR4, MyD88, IKKβ, p-P65, and p-IκBα in the liver and upregulated the protein expression levels of ZO-1, occludin, and claudin-4 in the jejunum. Moreover, DHA-PC treatment alleviated intestinal dysbiosis caused by HFD. At the genus level, DHA-PC promoted the relative abundances of unclassified Muribaculaceae, Lachnospiraceae NK4A136 group, Blautia, and unclassified Clostridia UCG-014, while reducing the abundance of Allobaculum, unclassified Atopobiaceae, Alistipes, Faecalibaculum, Lachnoclostridium, and Tuzzerella. Our findings suggest that DHA-PC alleviated HFD-induced NAFLD by regulating lipid metabolism and dysbiosis via the gut-liver axis.

Construction of Glycogen-Based Nanoparticles Loaded with Resveratrol for the Alleviation of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease.

The purpose of this study was to construct a glycogen (Gly)-based nanoparticle (NP) with liver-targeted and redox response to effectively deliver resveratrol (Res) for improving nonalcoholic fatty liver disease (NAFLD). Herein, Gly was modified using α-lipoic acid (α-LA) and lactobionic acid (Lac) to obtain an amphiphilic polymer (Gly-LA-Lac), which was self-assembled in water and then encapsulated in Res to form Res NPs with excellent stability. As expected, the Res NPs exhibited liver-targeted and redox response release behavior. In vitro cell studies demonstrated that the nanocarrier treatment enhanced the cellular uptake of Res and reduced oxidative stress and inflammatory factor levels. Meanwhile, the in vivo tests proved that the nanocarriers effectively reduced hepatic lipid accumulation and oxidative stress levels via regulating the TLR4/NF-κB signal pathway to improve liver damage in NAFLD mice. In conclusion, this study provides a promising strategy through the construction of Gly-based nanocarriers for the encapsulation of Res to effectively alleviate the process of NAFLD.

N-Acetyl Cysteine Ameliorates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease and Intracellular Triglyceride Accumulation by Preserving Mitochondrial Function.

Rationale: Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic disease characterized by liver steatosis. Excessive reactive oxygen species (ROS) originating from dysfunctional mitochondria is the major pathophysiological contributor in the development of NAFLD and is thought to be a promising therapeutic target. A few reports demonstrate the antioxidative treatments for NAFLD.Methods: Male C57 mice were fed on a normal chow diet (ND) or high-fat diet (HFD) for 8 weeks. PBS or N-acetyl cysteine (NAC) was gavaged to mice. LO2 human liver cell line treated with palmitic acid (PA) was applied as a cellular model. Western blot, immunofluorescence, biochemistry assay, and pathological staining were used to investigate the mechanism of suppressing lipid accumulation of NAC.Results: NAC treatment was able to prevent HFD-induced NAFLD, as evidenced by less hepatic triglyceride accumulation and lipid droplet formation compared with that of mice in the HFD group. NAC could preserve mitochondrial function by inhibiting excessive mitophagy and promoting mitochondria biogenesis to prevent ROS production. NAC also activated Sirt1 and preserved its protein level and subsequently promoted mitochondria biogenesis via deacetylating PGC1a.Conclusion: We demonstrated that NAC may be an effective drug to treat NAFLD, which was related to its antioxidative and mitochondrial protective effect.