INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 2
·1593
·
IF 5.6
Ji Ma,Yang Deng,Tingting Yang,Maoru Li,Jing Shang
Non-alcoholic fatty liver disease (NAFLD), defined in recent years as metabolic-associated fatty liver disease (MAFLD), is one of the most common liver diseases in the world, with no drugs on market. Esculetin (ESC) is an active compound discovered in a variety of natural products that modulates a wide range of metabolic diseases and is a potential drug for the treatment of NAFLD. In this study, we used an HCD-induced NAFLD larval zebrafish model in vivo and an FFA-induced BRL-3A hepatocyte model in vitro to evaluate the anti-NAFLD effect of ESC. Lipid lowering, anti-oxidation and anti-inflammation effects were revealed on ESC and related gene changes were observed. This study provides a reference for further study and development of ESC as a potential anti-NAFLD/MAFLD drug.Keywords:esculetin;non-alcoholic fatty liver disease;lipid-lowering;antioxidant
研究领域:
药理学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2023
·
IF 7.2
Li Luo,Huafeng Zhang,Weiliang Chen,Ziming Zheng,Zihao He,Haoyu Wang,Kaiping Wang,Yu Zhang
Angelica sinensis polysaccharide (ASP) showed increasingly recognized hepatoprotective effects and lipid regulation. Because polysaccharides are typically degraded into fragments or short-chain fatty acids in the gut, rather than being absorbed in their intact form, it is worth pondering why ASP can regulate hepatic lipid metabolism and protect the liver from damage caused by lipid accumulation. In vivo and in vitro nonalcoholic fatty liver disease (NAFLD) models with lipid accumulation were established to investigate the effect and potential mechanisms of ASP on hepatic fat accumulation. Our results showed that ASP remodeled the composition and abundance of the gut microbiota in high-fat diet-fed mice and increased their levels of propionate (0.92 ± 0.30 × 10 7 vs. 2.13 ± 0.52 × 10 7 ) and butyrate (1.83 ± 1.31 × 10 7 vs. 6.39 ± 1.44 × 10 7 ). Sodium propionate significantly increased the expression of estrogen-related receptor α (ERRα) in liver cells (400 mM sodium propionate for 2.19-fold increase) and alleviated the progress of NAFLD in methionine–choline-deficient diet model. Taken together, our study demonstrated that ASP can regulate hepatic lipid metabolism via propionate/ERRα pathway and ultimately relieving NAFLD. Our findings demonstrate that ASP can be used as a health care product or food supplement to prevent NAFLD.
研究领域:
药理学
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肝病学
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微生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 4
·e70097
·
IF 3.3
Wei-fang Song,Sheng-nan Li,Rui-xin Yao,Qiu-yan Jiang,Ting Shi,Dan-dan Fan,Hai-juan Zhang,Wen-hui Zhang,Rui-jun Wang
The primary objective aims to evaluate the therapeutic efficacy of echinacoside in ameliorating hepatic steatosis and exploring its role in modulating autophagic flux through AMP-activated protein kinase (AMPK) signaling, positioning it as a potential treatment for non-alcoholic fatty liver disease (NAFLD). A well-established NAFLD rat model was employed, administering varying concentrations of echinacoside. Biochemical parameters, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alongside liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), were measured to assess liver function. To elucidate the molecular mechanisms, western blot analyses were performed to assess the expressions of p-AMPK, total AMPK, and key autophagy markers LC-3 I/II and Beclin-1. Echinacoside significantly improved the lipid profile by lowering plasma TG, TC, and LDL-C levels while increasing HDL-C. It also reduced serum ALT, AST, and ALP activities, demonstrating hepatoprotective effects. Notably, echinacoside reversed the p-AMPK levels in NAFLD rats in a dose-dependent manner, with the highest dosage showing the strongest effect. This was accompanied by increased expression of LC-3 I/II and Beclin-1. Echinacoside is expected to be a therapeutic drug for NAFLD by activating AMPK activity and enhancing autophagy to improve liver function. These findings suggest its clinical potential, with autophagy modulation via the AMPK pathway as a possible therapeutic mechanism for NAFLD treatment.
研究领域:
药理学
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代谢生物学
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肝脏疾病研究
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DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2025
·
IF 10.5
Mengdi Zhang,Jinliang Ji,Yuanyuan Lei,Fujian Qin,Yitong Tao,Ning Li,Jinlei Bian,Zhiyu Li,Maode Lai,Zhixia Qiu
Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggest ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction—a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.
研究领域:
生物化学
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代谢疾病
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肝脏研究
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DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2025
·
IF 4.6
Qian Wang,Dongmei Li,Ze Zhang,Lingyi Shen,Hong Xu,Zhiyong Wang,Carl Redshaw,Qilong Zhang
Non-alcoholic fatty liver disease (NAFLD) is a disease closely associated with metabolic abnormalities. Lipid droplets (LDs) serve as organelles that store intracellular neutral lipids and maintain cellular energy homeostasis. Their abnormalities can cause metabolic disorders and disease, which is also one of the distinctive characteristics of NAFLD patients. However, the correlation between the polarity of LDs and NAFLD is easily overlooked. To monitor the polarity changes in LDs in order to assess the progression of NAFLD, triphenylamine was used as the electron donor (D), pyridine as the electron acceptor (A) and thiazolo[5,4-d]thiazole (TTz) as π bridge in this study. The structure was modified by introducing different substituents at the triphenylamine to obtain a series of D-π-A structural polar-responsive asymmetric thiazolo[5,4-d]thiazole (aTTz) fluorescent probes with different push–pull electron effects and steric hindrance. The fluorescent probes, which exhibit distinct fluorescence emission spectra in solutions with varying polarities, demonstrate excellent polarity-sensitive properties, and the displacement of the maximum emission wavelength varies from 125 to 150 nm. Meanwhile, the fluorescent probes exhibited low dark toxicity of cells and can specifically image lipid droplets, with a localization coefficient of more than 0.84 when imaging, and can be applied to the fluorescence imaging of C. elegans . Furthermore, the polar response properties of the fluorescent probes were used to distinguish normal liver tissue and nonalcoholic fatty liver tissue by fluorescence lifetime microscopic imaging (FLIM), thus providing a molecular tool for the diagnosis of NAFLD.
研究领域:
生物化学
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医学影像学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Junli Wang,Yifei Guo,Xin Geng,Jingyu Hu,Minmin Yan,Yuanqiang Sun,Ke Zhang,Lingbo Qu,Zhaohui Li
Lipid droplets (LDs) play indispensable roles in numerous physiological processes; hence, the visualization of the dynamic behavior of LDs in living cells is of great importance in physiological and pathological research. In this article, the quantitative structure–activity relationship (QSAR) theory was employed as an effective design strategy for the development of organelle-targeting carbon dots (CDs). The lipid–water partition coefficient (Log P) of the QSAR was adopted as a key parameter to predict the cellular uptake and subcellular localization of CDs in live cells. By carefully adjusting the molecular structure and lipophilicity of the precursors, p-phenylenediamine-derivatized nucleolus-targeting hydrophilic CDs were converted to lipophilic CDs [4-piperidinoaniline (PA) CDs] with inherent LD-targeting performance. The PA CDs were able to indicate the dynamic behavior of LDs and visualize the changes of bisphenol A-induced nonalcoholic fatty liver disease-like changes in a cellular model. The QSAR strategy of CDs demonstrated here is expected to be increasingly exploited as a powerful design tool for developing various organelle-targeting CDs.
研究领域:
细胞生物学
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分子生物学
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生物成像
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DOI
PubMed
高影响因子
Foods
·
2025
·Vol. 14
·期 10
·1707
·
IF 5.1
Li Li,Ying Hu,Yu-Mei Wang,Xiao-Xue Wu,Si-Tong Lin,Hang Li,Ji Zhang,Guo-Rong Fan,Zong-De Wang,Bin Wang,Shang-Xing Chen
In this study, we systematically investigated the mechanisms of the antioxidation and anti-lipid accumulation effects of antioxidant peptides fromLitsea cubebaon a free fatty acid (FFA)-induced NAFLD model of HepG2 cells. The NAFLD cell model was constructed by inducing the HepG2 hepatocellular carcinoma cell line with 0.5 mmol/L FFAs, and AQRDAGLL, QEGPFVR, and DVPPPRGPL were given to the culture to study their lipid-lowering and antioxidant activities on NAFLD cells. The lipid-lowering activities of the three antioxidant peptides were evaluated by Oil Red O staining and TG and TC content assays, and the results showed that all three peptides had strong ameliorating effects on FFA-induced lipid accumulation in NAFLD cells. The intracellular antioxidant protease (CAT, GSH, and SOD) activity levels and lipid peroxidation (MDA) content were measured and intracellular ROS levels were detected. The results showed that after intervention with the antioxidant peptides, the intracellular ROS levels in the NAFLD model cells were significantly reduced, the SOD and CAT activities were increased, the GSH content was elevated, and the MDA content was reduced, which indicated that AQRDAGLL, QEGPFVR, and DVPPPRGPL were able to inhibit the oxidative stress of the cells effectively and to achieve the effect of intervening in NAFLD. JC-1 fluorescence staining experiments showed that the mitochondrial membrane potential function of NAFLD cells was restored under the effect of the antioxidant peptides. Molecular dynamics simulations revealed that the main driving force between QEGPFVR and Keap1 protein was van der Waals forces, ΔG = −62.11 kcal/mol, which indicated that QEGPFVR was capable of spontaneously binding to Keap1 protein.
研究领域:
生物化学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2020
·
IF 4.192
Zi-Rui Huang,Jia-Cong Deng,Qiu-Yi Li,Ying-Jia Cao,Yi-Chen Lin,Wei-Dong Bai,Bin Liu,Ping-Fan Rao,Li Ni,Xu-Cong Lv
This study aimed to investigate the protective mechanism of common buckwheat (Fagopyrum esculentum Moench.) against nonalcoholic fatty liver disease (NAFLD) associated with dyslipidemia in mice that were fed a high-fat and high-cholesterol diet (HFD). Results showed that oral supplementation of common buckwheat significantly improved physiological indexes and biochemical parameters related to dyslipidemia and NAFLD in mice fed with HFD. Furthermore, the HFD-induced reductions in fecal short-chain fatty acids were reversed by common buckwheat intervention, which also increased the fecal bile acid (BA) abundance compared with HFD-induced hyperlipidemic mice. Liver metabolomics based on ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry demonstrated that common buckwheat supplementation made significant regulatory effects on the pentose phosphate pathway, starch and sucrose metabolism, primary BA biosynthesis, and so forth. The results of high-throughput sequencing revealed that common buckwheat supplementation significantly altered the structure of the intestinal microbiota in mice fed with HFD. The correlations between lipid metabolic parameters and intestinal microbial phylotypes were also revealed by the heatmap and network. Additionally, common buckwheat intervention regulated the mRNA expressions of genes responsible for liver lipid metabolism and BA homeostasis, thus promoting BA synthesis and excretion. These findings confirmed that common buckwheat has the outstanding ability of improving lipid metabolism and could be used as a potential functional food for the prevention of NAFLD and hyperlipidemia.
研究领域:
营养学
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代谢组学
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肝脏病学
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食品科学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 7
·3898-3915
·
IF 5.882
Li Zhang,Sheng-Ye Yang,Feng-Rong Qi-Li,Xiao-Xiao Liu,Wei-Tao Zhang,Chao Peng,Ping Wu,Ping Li,Pingping Li,Xiaojun Xu
Isoliquiritigenin (ISO) is a flavonoid extracted from the root of licorice, which serves various biological and pharmacological functions including antiinflammatory, antioxidation, liver protection, and heart protection. However, the mechanism of its action remains elusive and the direct target proteins of ISO have not been identified so far. Through cell-based screening, we identified ISO as a potent lipid-lowering compound. ISO treatment successfully ameliorated fatty acid-induced cellular lipid accumulation and improved nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) by increasing PPARα-dependent lipid oxidation and decreasing SREBPs-dependent lipid synthesis. Both these signaling required the activation of SIRT1. Knockdown of SIRT1 resulted in the reversal of ISO beneficiary effects suggesting that the lipid-lowering activity of ISO was regulated by SIRT1 expression. To identify the direct target of ISO, limited proteolysis combined with mass spectrometry (LiP-SMap) strategy was applied and IQGAP2 was identified as the direct target for ISO in regulating lipid homeostasis. In the presence of ISO, both mRNA and protein levels of SIRT1 were increased; however, this effect was abolished by blocking IQGAP2 expression using siRNA. To explore how IQGAP2 regulated the expression level of SIRT1, proteome profiler human phospho-kinase array kit was used to reveal possible phosphorylated kinases and signaling nodes that ISO affected. We found that through phosphorylation of CREB, ISO transduced signals from IQGAP2 to upregulate SIRT1 expression. Thus, we not only demonstrated the molecular basis of ISO in regulating lipid metabolism but also exhibited for the first time a novel IQGAP2-CREB-SIRT1 axis in treating NAFLD/NASH.
研究领域:
药理学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2025
·Vol. 20
·期 5
·e0324164
·
IF 2.6
Bingbing Cao,Jiali Zhou,Bo Xia,Xiaoqing Li,Rui Wang,Yiqiao Xu,Chunqi Li
Choline has been proven to be effective in maintaining liver function. However, the effect of choline, in combination with other nutrients, on the improvement of non-alcoholic fatty liver disease (NAFLD) remains unclear. This study aimed to investigate the potential effect of the nutraceutical complex containing choline bitartrate, zinc citrate, and dl-α-Tocopheryl acetate on NAFLD in the zebrafish model. The NAFLD model was induced in zebrafish by administering thioacetamide. Experimental groups were established, including a normal control group, the model control group, the positive control group, the nutraceutical complex intervention group, and the choline bitartrate alone intervention group. The intervention was administered to the zebrafish in a water-soluble form, while the positive control group received polyene phosphatidylcholine at a concentration of 50.0 μg/mL. Notably, the protective effect of the nutraceutical complex against NAFLD is more pronounced than that observed with choline bitartrate supplementation alone. The results of transcriptomics and quantitative real-time PCR showed that the potential mechanisms underlying the effects of the nutraceutical complex might involve the upregulation of acacia, acsl1a , fbp2 gene expression, and the downregulation of tbc1d1 gene expression. These results were further validated by western blotting and overexpression experiments. Our findings indicated that choline bitartrate, zinc citrate, and dl-α-Tocopheryl acetate can help improve NAFLD. The results of this study provide evidence for the application of the nutraceutical complex in the improvement of NAFLD.
研究领域:
营养学
·
肝脏病理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2019
·Vol. 11
·期 1
·977-991
·
IF 3.241
Lihua Song,Yating li,Dan Qu,Pengling Ouyang,Xinwen Ding,PeiYing Wu,Qi Guan,Li Yang
Recent studies have shown that the occurrence and progression of nonalcoholic fatty liver disease (NAFLD) can be aggravated by dysregulation of intestinal flora. We previously found that phytosterol esters (PSEs) could effectively prevent the progression of NAFLD. Here, we further investigated the regulatory effect that PSEs have on gut flora and faecal metabolites in rats with NAFLD. Adult SD (Sprague Dawley) rats were randomized into four groups: the normal chow diet (NC), high-fat diet (HFD), low-dose PSE (0.05 g per 100 g BW, PSEL) and high-dose PSE (0.10 g per 100 g BW, PSEH) groups. PSEs were intragastrically administered once a day for 12 consecutive weeks. Our work indicated that high-dose PSE treatment effectively inhibited the increase in liver and abdominal fat indexes (P < 0.01) and hepatic lipids (P < 0.01); a high dose PSE treatment effectively corrected the HFD-induced intestinal flora imbalance by changing the diversity. The relative abundances of the four phyla (Firmicutes, Proteobacteria, Actinobacteria and Verrucomicrobia) and partial bacteria at the genus level (Faecalibacterium, Akkermansia, etc.) in the PSEH group were closer to those in the NC group. High-dose PSE intervention significantly increased the relative abundance of Bacteroidetes and Anaerostipes. Compared with the HFD, PSEH treatment significantly decreased the ionic strengths of bile acid metabolism products (P < 0.05), which were positively correlated with hepatic steatosis. In conclusion, PSE treatment exerts a beneficial effect on NAFLD that is associated with its regulatory action on intestinal flora and faecal metabolites, which might present a new opportunity to develop effective and safe preventive strategies against NAFLD.
研究领域:
营养学
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微生物学
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肝病学
✓ 已验证
DOI
PubMed
高影响因子
Food Science & Nutrition
·
2020
·Vol. 8
·期 7
·3212-3224
·
IF 1.797
Ping Ma,Congyong Sun,Wenjing Li,Wenwen Deng,Michael Adu-Frimpong,Jiangnan Yu,Ximing Xu
Nonalcoholic fatty liver disease (NAFLD) is one of the prevalent and typical chronic liver diseases. In this study, we extracted a novel Angelica sinensis polysaccharide (ASP) with low molecular weight (MW) of 3.2 kDa through optimized “one-step” purification process. The major monosaccharide components of ASP were mannose, rhamnose, glucuronic acid, galactose, arabinose, and xylose with weight ratio of 0.23:0.17:14.41:0.39:1.68:0.87, respectively. Herein, “small” ASP could serve as an effective therapeutic option for NAFLD both in free fatty acid-induced L02 models and in high-fat diet-induced mice models. Results revealed that low MW ASP dose-dependently decreased TG, TC in vitro and TG, TC, ALT, HDL-C, and LDL-C in vivo. Oil Red O-positive area and Nile red fluorescence intensity decreased in ASP treatment groups both in vitro and in vivo which suggested ASP could reduce lipid accumulation and fatty regeneration. Hematoxylin–eosin staining results shown a decrease in hepatocytes ballooning indicating that ASP could ameliorate liver lipid degeneration. Briefly, a novel polysaccharide with low MW was successfully obtained which can prospectively act as NAFLD therapy.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）