Metabolites
·
2021
·Vol. 11
·期 6
·374
·
IF 4.932
Nanlin Zhu,Suling Huang,Qingli Zhang,Zhuohui Zhao,Hui Qu,Mengmeng Ning,Ying Leng,Jia Liu
The pathophysiology of nonalcoholic fatty liver disease (NAFLD) is a complex process involving metabolic and inflammatory changes in livers and other organs, but the pathogenesis is still not well clarified. Two mouse models were established to study metabolic alteration of nonalcoholic fatty liver and nonalcoholic steatohepatitis, respectively. The concentrations of metabolites in serum, liver and intestine content were measured by the AbsoluteIDQ®p180 Kit (Biocrates Life Sciences, Innsbruck, Austria). Multivariate statistical methods, pathway analysis, enrichment analysis and correlation analysis were performed to analyze metabolomic data. The metabolic characteristics of liver, serum and intestine content could be distinctly distinguished from each group, indicating the occurrence of metabolic disturbance. Among them, metabolic alteration of liver and intestine content was more significant. Based on the metabolic data of liver, 19 differential metabolites were discovered between DIO and control, 12 between DIO-CCl4and DIO, and 47 between DIO-CCl4and normal. These metabolites were mainly associated with aminoacyl-tRNA biosynthesis, nitrogen metabolism, lipid metabolism, glyoxylate and dicarboxylate metabolism, and amino metabolism. Further study revealed that the intervention of obeticholic acid (OCA) could partly reverse the damage of CCl4. The correlation analysis of metabolite levels and clinical parameters showed that phosphatidylcholines were negatively associated with serum alanine aminotransferase, aspartate aminotransferase, NAFLD activity score, and fibrosis score, while lysophosphatidylcholines, sphingomyelins, amino acids, and acylcarnitines shared the reverse pattern. Our study investigated metabolic alteration among control, NAFLD model, and OCA treatment groups, providing preclinical information to understand the mechanism of NAFLD and amelioration of OCA.Keywords:nonalcoholic fatty liver disease (NAFLD);nonalcoholic fatty liver (NAFL);nonalcoholic steatohepatitis (NASH);differential metabolites;metabolic pathways;obeticholic acid (OCA)
研究领域:
代谢组学
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肝脏疾病
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药理学
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产品关联
DOI
PubMed
高影响因子
PLANTA MEDICA
·
2020
·Vol. 86
·期 04
·255-266
·
IF 2.687
Nan Xu,Xue Wu,Hui-Juan Luo,Fang-Fang Xu,Qiong-Hui Huang,Jia-Zhen Wu,Yu-Xuan Gan,Min-Yao Li,Zheng-Quan Lai,Hui-Ran Lin,Jian-Nan Chen,Zi-Ren Su,Wei-Peng Ai,Yu-Hong Liu
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Nevertheless, no first-line therapy exists. Hepatic steatosis is the earliest stage of NAFLD, which is characterized by an accumulation of hepatic lipids. Patchouli oil (PO), which is isolated from the well-known Chinese herb named Pogostemon cablin (Blanco) Benth. (Lamiaceae), inhibits hepatic lipid accumulation effectively. However, its potential ability for the treatment of NAFLD had not been reported before. Thus, the objective of this study was to investigate the effectiveness of PO against hepatic steatosis and its underlying mechanisms. We used a high fat diet (HFD)-induced hepatic steatosis model of rats to estimate the effect of PO against NAFLD. Hematoxylin-eosin and oil red O staining were used to analyze the hepatic histopathological changes. ELISA, RT-qPCR, and Western blotting analysis were applied to evaluate the parameters for hepatic steatosis. Our results showed that PO significantly attenuated the lipid profiles and the serum enzymes, evidenced by quantitative and histopathological analyses. It also markedly down-regulated the expression of sterol regulatory element-binding protein 1 (SREPB-1c) with its downstream factors in de novo lipogenesis. And, likewise, in lipid export by very low-density lipoproteins (VLDL), related molecules were dramatically improved. Furthermore, PO observably normalized the aberrant peroxisome proliferator-activated receptor α (PPAR-α) signal in fatty acids oxidation. In conclusion, PO exerted a preventing effect against HFD-induced steatosis and might be due to decrease de novo lipogenesis, promote export of lipids, as well as owing to improve fatty acids oxidation.
研究领域:
药理学
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肝病学
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代谢性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF NUTRITION
·
2023
·
IF 3.6
Naiyan Lu,Xue Mei,Xu Li,Xue Tang,Guofeng Yang,Wen Xiang
Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder, affecting approximately 25 % of the population. Coffee-drinking obese smokers exhibit lower body weights and decreased NAFLD rates, but the reasons behind this remain unclear. Additionally, the effect of nicotine, the main component of tobacco, on the development of NAFLD is still controversial. Our study aimed to explore the possible reasons that drinking coffee could alleviate NAFLD and gain weight and identify the real role of nicotine in NAFLD of obese smokers. A NAFLD model in mice was induced by administering nicotine and a high-fat diet (HFD). We recorded changes in body weight and daily food intake, measured the weights of the liver and visceral fat, and observed liver and adipose tissue histopathology. Lipid levels, liver function, liver malondialdehyde (MDA), superoxide dismutase (SOD), serum inflammatory cytokine levels and the expression of hepatic genes involved in lipid metabolism were determined. Our results demonstrated that nicotine exacerbated the development of NAFLD and caffeine had a hepatoprotective effect on NAFLD. The administration of caffeine could ameliorate nicotine-plus-HFD-induced NAFLD by reducing lipid accumulation, regulating hepatic lipid metabolism, alleviating oxidative stress, attenuating inflammatory response and restoring hepatic functions. These results might explain why obese smokers with high coffee consumption exhibit the lower incidence rate of NAFLD and tend to be leaner. It is essential to emphasise that the detrimental impact of smoking on health is multifaceted. Smoking cessation remains the sole practical and effective strategy for averting the tobacco-related complications and reducing the risk of mortality.
研究领域:
肝病学
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营养学
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药理学
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公共卫生
✓ 已验证
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Xiaohong Liu,Xiaoyu Li,Shan Su,Yujia Yuan,Wen Liu,Min Zhu,Qing Zheng,Xin Zeng,Fudong Fu,Yanrong Lu,Younan Chen
Lipotoxicity caused by excess free fatty acids , particularly saturated fatty acids (SFAs) such as palmitic acid (PA), is one of the most important pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, unsaturated fatty acids (UFAs), such as oleic acid (OA), are nontoxic and can combat SFA-induced toxicity through alleviation of cell apoptosis, endoplasmic reticulum stress (ER stress) and lipids metabolism disorder. However, whether OA is able to regulate autophagy is largely unknown. So, this study aims to investigate the mechanism underlying OA mediated modulation of autophagy in hepatocytes and mice with NAFLD. In vitro, human hepatoma cell line HepG2 cells, human normal liver cells L-02 and mouse normal liver cells AML12 were treated with palmitic acid (PA)/tunicamycin (TM) or/and OA for 48 h. In vivo, C57/BL6 mice were fed with high fat diet (HFD) to induce NAFLD. And the HFD was partial replaced by olive oil to observe the protective effects of olive oil. We demonstrated that PA/TM impaired cell viability and induced cellular apoptosis in HepG2 cells and L-02 cells. Moreover, PA/TM induced autophagy impairment by reducing the nuclear translocation of transcription factor EB (TFEB) and inhibiting the activity of CTSB. However, OA substantially alleviated PA/TM induced cellular apoptosis and autophagy dysfunction in hepatocytes. Additionally, restoring autophagy function is able to reduce ER stress. Similarly, HFD for 20 weeks successfully established NAFLD model in C57/BL6 mice, and significant autophagy impairment were observed in liver tissues. Noteworthily, 30% replacement of HFD with olive oil had profoundly reversed NAFLD. It significantly impoved steatosis, and reduced autophagy dysfunction, ER stress and apoptosis in liver tissue. Conclusively, these data demonstrated that OA is able to effectively impove autophagy dysfunction under the context of both PA and ER stress inducer induced lipotoxicity, and OA mediated regulation of lysosome dysfunction through TFEB plays an important role, suggesting that the regulation of ER stress-autophagy axis is a critical mechanism in OA driven protection in NAFLD.
研究领域:
肝病学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Yi Chu,Sisi Gui,Yazhen Zheng,Jingwu Zhao,Yaxiang Zhao,Yingying Li,Xiaodong Chen
Non-alcoholic fatty liver disease (NAFLD) is closely associated with the body's energy metabolism. A potential strategy to regulate energy metabolism, combat obesity, and reduce NAFLD is by enhancing adipocyte thermogenesis and increasing energy expenditure. In this study, our objective was to examine the effects of phenolic extracts derived from Magnolia officinalis on the regulation of NAFLD. Specifically, we investigated the impact of Magnolol or Honokiol treatment on high-fat diet (HFD)-induced obese C57BL6/J male mice. Firstly, we monitored energy metabolism, dissected tissues, and analyzed tissue sections. Additionally, we conducted experiments on HepG2 and primary adipocytes to gain insights into the roles of Magnolol or Honokiol. To further understand the effects of these compounds on related signaling pathways and marker genes, we performed molecular docking, dual-luciferase assays, and interfered with target genes. Our findings revealed that Magnolol or Honokiol activate the peroxisome proliferator activated receptor alpha (PPARα) signaling pathway, leading to the alleviation of NAFLD. This activation promotes fatty acid oxidation, reduces lipogenesis, and enhances the expression and secretion of FGF21. Notably, Fibroblast growth factor 21 (FGF21), secreted by the liver, plays a crucial role in improving communication between the liver and adipocytes while also promoting the browning of adipose tissue. Additionally, Magnolol or Honokiol activate the peroxisome proliferator activated receptor gamma (PPARγ) signaling pathway, resulting in increased uncoupling protein 1 (UCP1) expression, heightened heat production in adipose tissue, and anti-obesity. Therefore, Magnolol or Honokiol alleviate NAFLD, promote adipose tissue browning and resist obesity through dual activation of PPARα/γ.
研究领域:
药理学
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代谢
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分子生物学
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营养学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL FOOD
·
2024
·
IF 1.7
Ruixi Luo,Yudie Hu,La Wang,Wenjia Wang,Ping Wang,Zunli Ke,Didong Lou,Weiyi Tian
It is currently thought that excess fatty acid-induced lipotoxicity in hepatocytes is a critical initiator in the development of nonalcoholic fatty liver disease (NAFLD). Lipotoxicity can induce hepatocyte death; thus, reducing lipotoxicity is one of the most effective therapeutic methods to combat NAFLD. Abundant evidence has shown that hesperidin (HSP), a type of flavanone mainly found in citrus fruits, is able to ameliorate NAFLD, but the molecular mechanisms are unclear. We previously reported that pyroptosis contributed to NAFLD development and that inhibiting pyroptosis contributed to blunting the progression of NAFLD in rat models. Therefore, we questioned whether HSP could contribute to ameliorating NAFLD by modulating pyroptosis. In this study, a high-fat diet (HFD) induced dyslipidemia and hepatic lipotoxicity in rats, and HSP supplementation ameliorated dyslipidemia and insulin resistance. In addition, the HFD also caused pyroptosis in the liver and pancreas, while HSP supplementation ameliorated pyroptosis. In vitro, we found that HSP ameliorated palmitic acid-induced lipotoxicity and pyroptosis in HepG2 and INS-1E cells. In conclusion, we showed for the first time that HSP has a protective effect against liver and pancreas damage in terms of pyroptosis and provides a novel mechanism for the protective effects of HSP on NAFLD.
研究领域:
药理学
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营养学
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肝病学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Science and Human Wellness
·
2024
·
IF 5.6
Xianghui Huang,Jia Xu,Ye Xu,Bingxin Huangfu,Feng Zhang,Yanzhou Hu,Ruxin Gao,Xinxin Ren,Boyang Zhang,Kunlun Huang,Xiaoyun He
Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public health. However, to date, no approved therapeutic drugs have been developed. Dietary interventions with natural products have shown promise in preventing and treating NAFLD. Sulforaphane (SFN) is a phytocompound with antioxidant and anti-inflammatory properties, and previous research has demonstrated that SFN can ameliorate hepatic lipid accumulation and inflammation. However, the molecular mechanisms underlying these beneficial effects remain unclear. In this study, we confirmed the protective effects of SFN on excessive lipid accumulation and inflammatory injury in a high-fat, high-fructose diet-induced non-alcoholic steatohepatitis (NASH) mouse model. We found that SFN attenuates the inflammatory injury in a macrophage cell line and the liver of NASH mice, owing to the promotion of M1-type macrophage polarization toward the M2-type and the regulation of inflammatory mediators. Further analysis demonstrated that this SFN-induced macrophage M2-type polarization occurs in a Krüppel-like factor 4 (KLF4)-dependent manner. In summary, we uncovered a new mechanism of action underlying SFN activity and provide evidence that dietary intervention with SFN might be protective against NASH.
研究领域:
肝病学
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免疫学
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药理学
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营养学
✓ 已验证
产品关联
DOI
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2019
·
IF 3.061
Jianying Bai,Zhen He,Yaofu Li,Xuexia Jiang,Hongmei Yu,Qing Tan
Mono-2-ethylhexyl phthalate (MEHP) is a major bioactive metabolite in the widely used industrial plasticizer diethylhexyl phthalate (DEHP) that has been found to be toxic to the liver. The aim of this study is to determine whether MEHP exposure can change the expression of fatty acid metabolism-related genes in HepG2 cells, which might be related to non-alcoholic fatty liver disease (NAFLD). The results revealed that exposure to MEHP promoted lipid accumulation in HepG2 cells. The levels of intracellular triglycerides in the hepatocytes increased after exposure to 0.8–100 μM MEHP for 24 h and 48 h. The genetic expressions of SREBP-1c, ChREBP, ACC1, FASN, and SCD significantly increased at 6 h after exposure to MEHP. At 24 h, the expression of the SREBP-1c and ChREBP genes remained increased, while the expression of the FASN and SCD genes decreased. At 48 h, the expression of SREBP-1c, ChREBP, ACC1, FASN, and SCD decreased. Furthermore, the levels of proteins including ACC1, FASN, SCD, and ChREBP (except SREBP-1c) increased at 24 h. These findings suggest that MEHP exposure can promote fatty acid synthesis in hepatocytes by regulating the expression of relevant genes and proteins, contributing to NAFLD.
研究领域:
毒理学
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细胞生物学
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分子生物学
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肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2017
·
IF 3.649
Guangfei Wei,Xu Song,Yao Fu,Tao Gong,Quan Zhang
As a mitochondrial uncoupler, 2,4-dinitrophenol (DNP) is proven therapeutically effective against nonalcoholic fatty liver disease (NAFLD) by uncoupling oxidation and phosphorylation. However, a major factor that impedes the clinical application of DNP is the significant side effects derived from its frequent hyperthermia and even death. In this study, we developed an injectable liquid crystal gel (DNP-LC-gel) to reduce the toxicity of DNP. DNP-LC-gel achieved sustained release and maintained DNP plasma concentration at an effective drug level. In a rat model of NAFLD, DNP-LC-gel treated rats reduced hepatic steatosis , liver triglyceride content, plasma triacylglycerol (TG) and total cholesterol (TC) content. Compared with DNP solution (DNP-soln), rats after DNP-LC-gel treatment showed no body temperature toxicity and local irritation. All results above indicated that DNP-LC-gel has a great potential for NAFLD therapy.
研究领域:
药理学
·
肝病学
·
代谢性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 24
·12883-12895
·
IF 6.317
Wei Liu,Taili Shao,Lei Tian,Zhengrui Ren,Lan Gao,Zhiyan Tang,Zheng Fang,Pingchuan Yuan,Chunyan Liu,Jikun Li,Guodong Wang,Jun Han
The chemical structure and pharmacological activity of Polygonatum cyrtonema Hua polysaccharides have garnered significant attention in recent years. In this study, a homogeneous polysaccharide, PCP1, was extracted from P. cyrtonema Hua rhizomes and purified. Monosaccharide composition analysis showed that PCP1 is primarily composed of fructose, glucose, and mannose. Chemical structure analysis showed that the main chain of PCP1 is composed mainly of →1)-β-D-Fruf-(2→ and →1,6)-β-D-Fruf-(2→, with small amounts of →6)-α-D-Glcp-(1→, →4)-β-D-Manp-(1→, and β-D-Glcp-(1→. The side chain is β-D-Fruf-(2→ linked at C-6 of →1,6)-β-D-Fruf-(2→. In vivo experiments showed that PCP1 mitigates liver pathological damage, improves abnormal lipid metabolism and oxidative stress, promotes the production of short-chain fatty acids, and balances the composition of the intestinal microbiota in non-alcoholic fatty liver disease (NAFLD) mice. Thus, PCP1 can be used as a natural ingredient in functional foods for the treatment of NAFLD.
研究领域:
药理学
·
生物化学
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营养学
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胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Mengjie Kong,Yan Peng,Liyan Qiu
Non-alcoholic fatty liver disease (NAFLD) is currently a common chronic liver disease worldwide. By now, however, there isn't any FDA-approved specific drug for NAFLD treatment. It has been noticed that farnesoid X receptor (FXR), miR-34a and Sirtuin1 (SIRT1) is related to the occurrence and development of NAFLD. A oligochitosan-derivated nanovesicle (UBC) with esterase responsive degradability was designed to co-encapsulate FXR agonist (obeticholic acid, OCA) and miR-34a antagomir (anta-miR-34a) into the hydrophobic membrane and the center aqueous lumen of nanovesicles, respectively, by dialysis method. The action of UBC/OCA/anta-miR-34a loop on the regulation of lipid deposition via nanovesicles was evaluated on high-fat HepG2 cells and HFD-induced mice. The obtained dual drug-loaded nanovesicles UBC/OCA/anta-miR-34a could enhance the cellular uptake and intracellular release of OCA and anta-miR-34a, leading to the reduced lipid deposition in high-fat HepG2 cells. In NAFLD mice models, UBC/OCA/anta-miR-34a achieved the best curative effect on the recovery of body weight and hepatic function. Meanwhile, in vitro and vivo experiments validated that UBC/OCA/anta-miR-34a effectively activated the expression level of SIRT1 by enhancing the FXR/miR-34a/SIRT1 regulatory loop. This study provides a promising strategy for constructing oligochitosan-derivated nanovesicles to co-deliver OCA and anta-miR-34a for NAFLD treatment. Statement of significance This study proposed a strategy to construct oligochitosan-derivated nanovesicles to co-deliver obeticholic acid and miR-34a antagomir for NAFLD treatment. Based on the FXR/miR-34a/SIRT1 action loop, this nanovesicle effectively exerted a synergetic effect of OCA and anta-miR-34a to significantly regulate lipid deposition and recover liver function in NAFLD mice.
研究领域:
药学
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分子生物学
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肝病学
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纳米技术
✓ 已验证
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Lingyu Song,Yali Huang,Lu Liu,Xuebing Chang,Laying Hu,Guifang Wang,Lifen Xu,Tian Zhang,Yuanyuan Wang,Ying Xiao,Hong Yang,Suye Ran,Qing Shi,Tuanlao Wang,Mingjun Shi,Yuxia Zhou,Bing Guo
Amid a rising prevalence of non-alcoholic fatty liver disease (NAFLD), there is still an unmet need to better treat it. We identified a secreted factor, Meteorin-like (Metrnl), with decreased levels in livers with hepatic steatosis. Notably, recombinant Metrnl ameliorated hepatic steatosis in NAFLD mouse models. Mechanistically, Metrnl exerted dual effects by promoting triglyceride (TG) transportation by the phosphatidylinositol 3-kinase (PI3K)/Akt/Sp1/cytidylyltransferase α (CCTα) axis, thereby increasing the biosynthesis of phosphatidylcholine (PC) to facilitate TG secretion from the liver while facilitating AMP-activated protein kinase (AMPK)-dependent fatty acid oxidation (FAO). Exogenous injection of cytidine diphosphocholine (CDP)-choline, the production of CCTα, to increase PC synthesis, was shown to restore the inhibition of TG secretion in hepatic Metrnl-deficient (LKO-Met) mice. Combining CDP-choline and an AMPK activator was sufficient to rescue hepatic steatosis in LKO-Met mice. Collectively, these findings reveal unexpected roles of Metrnl as a factor in PC biosynthesis, TG secretion, and FAO, suggesting potential therapeutic application for NAFLD.
研究领域:
肝病学
·
分子生物学
·
代谢学
·
药理学
✓ 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）