BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Guanlin Wu,Yan Zhang,Bo Liang,Lianhong Yin,Meng Gao,Han Zhang,Youwei Xu,Xu Han,Yan Qi,Fang Liu,Lina Xu
Investigating and identifying pathogenic molecules of non-alcoholic fatty liver disease (NAFLD) has become imperative, which would serve as effective targets in the future. We established high-fat diet (HFD)-induced NAFLD model in mice and palmitic acid (PA)-induced model in mouse AML12 cells. The level of miR-218-5p was examined by qRT-PCR, and Elovl5 was identified as the potential target gene of miR-218-5p . The binding relationship between miR-218-5p and Elovl5 was validated by double luciferase reporter gene assay, and inhibition/overexpression of miR-218-5p in vitro . The functional mechanisms of miR-218-5p / Elovl5 in regulating lipogenesis in NAFLD were investigated in vivo and in vitro through gain- and loss-of-function studies. MiR-218-5p was significantly increased, and Elovl5 was decreased in model group. According to the double luciferase reporter and gene interference experiments in AML12 cells, Elovl5 was a target gene of miR-218-5p and its expression was regulated by miR-218-5p . The SREBP1-mediated lipogenesis signaling pathway regulated by Elovl5 was upregulated in model group. Moreover, silencing of miR-218-5p significantly upregulated Elovl5 expression, and suppressed SREBP1 signaling pathway in PA-induced AML-12 cells. Correspondingly, the cell injury, elevated TC, TG contents and lipid droplet accumulation were ameliorated. Furthermore, the effect of miR-218-5p on lipogenesis in vitro and in vivo was obstructed by si-Elovl5 , implicating that miR-218-5p promotes lipogenesis by targeting ELOVL5 in NAFLD. miR-218-5p could promote fatty acid synthesis by targeting Elovl5 , thereby accelerating the development of NAFLD, which is one of the key pathogenic mechanisms of NAFLD and provides a new molecular target for the management of NAFLD.
研究领域:
分子生物学
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肝病学
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病理学
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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2021
·
IF 4.451
Xian Zheng,Xiao-Gai Zhang,Yao Liu,Li-Ping Zhu,Xiao-Shuang Liang,Hui Jiang,Gao-Feng Shi,Yuan-Yuan Zhao,Zhi-Wei Zhao,Yuan Teng,Ke Pan,Jian Zhang,Zhi-Qi Yin
Arjunolic acid (AA), as the most abundant triterpenoid component in Cyclocarya paliurus (Batal) Iljinskaja, previously displayed delipidating effects in free fatty acid (FFA)-induced HepG2 steatosis cells. However, whether AA still possesses the ameliorative effects on nonalcoholic fatty liver disease (NAFLD) in normal hepatocytes and in vivo remains vacant and the detailed mechanisms are not defined. In vitro , AA dose-dependently alleviated lipid accumulation in FFA-challenged primary hepatocytes without cytotoxicity. In vivo , AA showed pleiotropic benefits, including attenuating adiposity, mitigating hepatic steatosis and inflammation, improving lipid disorders and insulin resistance, and restoring the impaired gut barrier. Mechanically, we found that AA indirectly activated Sirt1/AMPK-modulated lipid metabolism through elevating NAMPT-mediated NAD + level, and triggering autophagy, together mediating the lipid-lowering effects. Collectively, our results convey that AA can substantially mitigate NAFLD via indirectly activating Sirt1/AMPK signaling, inducing autophagy and restoring gut barrier, and will be considered as a promising candidate for NAFLD therapy.
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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营养学
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产品关联
DOI
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2026
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IF 8.3
Panyi Hu,Liping Su,Jinfeng Liu,Rui Zhao,Dong Wang,Jiahan Cheng,Xiaohe Tian
Reliable visualization of lipid droplet (LD) remodeling remains challenging because conventional LD probes often suffer from background fluorescence and limited photostability in lipid-rich cellular environments. Here, we developed LD-TTP, an LD-targeting fluorescent probe integrating aggregation-induced emission (AIE) and intramolecular charge transfer (ICT) properties. LD-TTP exhibits strong fluorescence activation, high selectivity, and excellent photostability, enabling robust imaging and quantitative analysis of LD dynamics in cell-based steatotic models. Using staged steatotic HepG2 cells, we found that LD remodeling was accompanied by stage-dependent changes in the spatial distribution of the amyloid-β (Aβ)-associated receptor low-density lipoprotein receptor–related protein 1 (LRP1). In early steatosis, LRP1 expression increased and became enriched around LDs, coinciding with enhanced uptake of exogenous Cy5-labeled Aβ. As steatosis progressed, LRP1 expression declined, and its LD-associated localization was lost, paralleling reduced Aβ uptake. A diacylglycerol acyltransferase 1 (DGAT1) inhibitor partially restored Aβ uptake in moderate-to-severe steatotic HepG2 cells. These findings provide cellular-level evidence for a stage-dependent relationship among LD remodeling, LRP1 alteration, and Aβ uptake in hepatocytes. Although the present results offer mechanistic clues at the cellular level, they do not fully capture the influence of the physiological microenvironment in vivo . Further animal studies will be required to determine whether these LD–LRP1–Aβ-associated changes are maintained under physiological conditions.
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DOI
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Huicui Liu,Tao Chen,Xiaoqing Xie,Xinlei Wang,Yiwen Luo,Nan Xu,Zhen Sa,Min Zhang,Zhifei Chen,Xinzhong Hu,Juxiu Li
Nonalcoholic fatty liver disease (NAFLD) is characterized by marked imbalances in lipid storage and metabolism. Because the beneficial health effects of cereal β-glucan (BG) include lowering cholesterol and regulating lipid metabolism, BG may alleviate the imbalances in lipid metabolism observed during NAFLD. The aim of our study was to investigate whether BG from highland barley has an effect on western diet-induced NAFLD in mice. Using lipidomics, we investigated the underlying mechanisms of BG intervention, and identified potential lipid biomarkers. The results reveal that BG (300 mg/kg body weight) significantly alleviated liver steatosis. Lipidomics analysis demonstrated that BG also altered lipid metabolic patterns. We were able to identify 13 differentially regulated lipid species that may be useful as lipid biomarkers. Several genes in the hepatic lipid and cholesterol metabolism pathways were also modulated. These findings provide evidence that BG ameliorates NAFLD by altering liver lipid metabolites and regulating lipid metabolism-related genes.
研究领域:
营养学
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肝病学
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脂质代谢
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Endocrine Metabolic & Immune Disorders-Drug Targets
·
2025
·Vol. 26
·期 1
·E18715303424915
·
IF 2
Wenbo Gong,Xueke Lu,Siying Weng
IntroductionJiangtang Decoction (JTD) demonstrates notable efficacy in managing Type 2 Diabetes Mellitus (T2DM) and Non-Alcoholic Fatty Liver Disease (NAFLD). This study aimed to elucidate JTD's causal targets and therapeutic mechanisms by integrating network pharmacology, Summary-data Mendelian Randomization (SMR), and molecular docking, complemented by in vitro validation.Materials and MethodsJTD's targets were cross-matched with genes associated with T2DM or NAFLD. SMR and co-localization analyses, utilizing eQTL and pQTL data, identified causal signals for each disease and their shared counterparts. GO/KEGG enrichment analyses were performed on these shared signals. Molecular docking assessed binding interactions. In vitro experiments, including ELISA (Enzyme-linked immunosorbent assay) and lipid staining, evaluated JTD's hypoglycemic/hypolipidemic effects, while PCR/immunofluorescence validated key molecular predictions in High-Glucose and High-Lipid (HGHL)-induced HepG2 cells.ResultsInitial network pharmacology identified 1107 JTD targets for T2DM and 1126 for NAFLD. SMR analyses revealed 78 eQTLs and 67 pQTLs for T2DM, and 40 eQTLs and 38 pQTLs for NAFLD. Eight shared causal genetic signals were identified: ADAMTS4, ALDH2, GLO1, CDH1, PDHB, PRKAB1, TCF4, and EP300. In vitro, JTD significantly attenuated hepatic gluconeogenesis and lipid deposition, downregulated IL-1β, and notably restored PRKAB1 expression in HepG2 cells treated with HGHL.DiscussionEnrichment analysis revealed shared processes, including membrane microdomains, oxidoreductase activity, and responses to nutrient and oxygen levels. PRKAB1 exhibited a strong binding affinity with the JTD component Salsalate.ConclusionThis study identified eight genes that are genetically predicted to be causal for the therapeutic effects of JTD on both T2DM and NAFLD, thereby establishing a genetic link between the conditions. These targets and associated pathways illuminate common underlying mechanisms, supporting JTD's potential for integrated treatment strategies and providing a basis for further investigation.
研究领域:
药理学
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遗传学
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生物信息学
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分子生物学
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中医中药
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内分泌学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2018
·
IF 2.064
Yinji Liang,Yupei Zhang,Yuanjun Deng,Shu Liang,Yifang He,Yanning Chen,Chan Liu,Chenli Lin,Li Han,Guifang Tu,Qinhe Yang
We evaluate the effects of the Chaihu-Shugan-San decoction on intestinal microbe dysbiosis and chronic metabolic inflammation via the NLRP3 pathway in NAFLD rats that were fed a high-fat diet. Twenty-four SD rats (male, six weeks old, 200 ± 20 g) were randomly divided into three groups: normal control group (NC group), high-fat diet-fed group (HFD group), and Chaihu-Shugan-San decoction intervention group (CH group). The NC group rats were given standard feed, the HFD group rats were all fed a high-fat diet (83% standard feed + 10% lard oil + 5% sucrose + 1.5% cholesterol + 0.5% cholate), and the CH group rats were given a HFD plus Chaihu-Shugan-San at 9.6 g•kg−1•d−1. Body composition, serum and liver lipids, inflammatory markers, intestinal microbial population, and the NLRP3 pathway-associated protein were assessed. The results showed that Chaihu-Shugan-San decoction significantly reduced body weight and total fat mass and the levels of serum LPS, TG, TNF-α, IL-1β, and IL-18, as well as liver TC, TG, TNF-α, IL-1β, and IL-18 (P < 0.05). The abundance of Enterobacteriaceae (0.375% versus 0.064%, P < 0.05), Staphylococcaceae families (0.049% versus 0.016%, P < 0.05) and Veillonella genus (0.096% versus 0.009%, P < 0.01) significantly decreased, whereas the abundance of Anaeroplasma genus (0.0005% versus 0.0178%, P < 0.01) significantly increased. The expression levels of NLRP3, ASC, and Caspase-1 were changed significantly (P < 0.05). In summary, the Chaihu-Shugan-San decoction modulated intestinal microbe dysbiosis, reduced fat accumulation, and alleviated inflammatory factor expression, which are all processes related to the NLRP3 inflammasome pathway in NAFLD rats.
研究领域:
药理学
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微生物学
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炎症研究
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Minghui Zhao,Hongfang Mu,Qian Ji,Jiale Song,Fuyixuan Zheng,Tianlong Liu,Wenbin Li,Rong Wang
Background The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored. Objective This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure. Methods Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α. Conclusion Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2022
·
IF 4.46
Zeyu Li,Kanglin Wu,Yi Zou,Wei Gong,Peng Wang,Hong Wang
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.
研究领域:
肝病学
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分子生物学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
Foods
·
2021
·Vol. 10
·期 12
·3022
·
IF 4.35
Meiyi Hu,Li Zhang,Zheng Ruan,Peiheng Han,Yujuan Yu
Gannannavel orange andJinggangpomelo, belonging to the genus Citrus, are good sources of phenolic compounds, which are mainly concentrated in the peel. These phenolic compounds are considered promising in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD). In order to maximize nutrients retention and bioactivity in the peel, pomelo peel and orange peel were processed using freeze-drying technology and mixed in the ratio (pomelo peel powder 50% and orange peel powder 50%) to make citrus peel powder (CPP). The purpose of this study was to explore new strategies and mechanisms associated with the consumption of CPP to alleviate nonalcoholic fatty liver injury, lipid metabolism disorders, and gut microbiota dysbiosis in obese mice induced by high-fat diet (HFD). The results showed that after 12 weeks of CPP administration, CPP supplementation had a strong inhibitory effect on HFD-induced weight gain, hepatic fat accumulation, dyslipidemia, and the release of pro-inflammatory cytokines. In particular, CPP modulates the composition of the intestinal flora, such as increasing the relative abundance of phylumFirmicutes, genusFaecalibaculum, genusLactobacillus, genusDubosiella, and genusLachnospiraceae_NK4A136_ groupand decreasing the relative abundance of phylumBacteroidota, genusHelicobacter, and genusBacteroides. These results suggest that CPP has a preventive effect on NAFLD, which can be related to the regulation of intestinal flora.Keywords:citrus peel;liver metabolites;gut flora;non-alcoholic fatty liver disease;pomelo;orange
研究领域:
营养学
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肝病学
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微生物组研究
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代谢组学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Qiushuang Sun,Qun Niu,Yating Guo,Yu Zhuang,Xiaonan Li,Jia Liu,Ning Li,Zhiyu Li,Fang Huang,Zhixia Qiu
Upregulated de novo lipogenesis (DNL) plays a pivotal role in the progress of the nonalcoholic fatty liver disease (NAFLD). Cytoplasmic citrate flux, mediated by plasma membrane citrate transporter (SLC13A5), mitochondrial citrate carrier (SLC25A1), and ATP-dependent citrate lyase (ACLY), determines the central carbon source for acetyl-CoA required in DNL. Curcumin, a widely accepted dietary polyphenol, can attenuate lipid accumulation in NAFLD. Here, we first investigated the lipid-lowering effect of curcumin against NAFLD in oleic and palmitic acid (OPA)-induced primary mouse hepatocytes and high-fat plus high-fructose diet (HFHFD)-induced mice. Curcumin profoundly attenuated OPA- or HFHFD-induced hyperlipidemia and aberrant hepatic lipid deposition via modulating the expression and function of SLC13A5 and ACLY. The possible mechanism of curcumin on the citrate pathway was investigated using HepG2 cells, HEK293T cells transfected with human SLC13A5, and recombinant human ACLY. In OPA-stimulated HepG2 cells, curcumin rectified the dysregulated expression of SLC13A5/ACLY possibly via the AMPK–mTOR signaling pathway. Besides, curcumin also functionally inhibited both citrate transport and metabolism mediated by SLC13A5 and ACLY, respectively. These findings confirm that curcumin improves the lipid accumulation in the liver by blocking citrate disposition and hence may be used to prevent NAFLD.
研究领域:
药理学
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分子生物学
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代谢紊乱
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DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2019
·Vol. 34
·期 3
·e4767
·
IF 1.748
Yong-hong Liu,Ting-ting Du,Jing-yuan Wan,Hua Zhao,Dan Huang,Jian-sha Li,Xin-hui Jiang
Disorders of certain branched-chain amino acids may be associated with the occurrence and development of non-alcoholic fatty liver disease. Measurement of related branched-chain amino acid levels could provide a reference for the clinical and scientific research of the non-alcoholic fatty liver disease. An established HPLC–FLD method was used to quantify aspartic acid, glutamate, glutamine, glycine, taurine, tyrosine, 4-amino butanoic acid, tryptophan, methionine, valine, phenylalanine, isoleucine and leucine in mouse brain tissue. Brain tissue samples mixed with internal standard (3-aminobutyric acid) were processed, then derivatized with 2- O -phthaldialdehyde, and finally separated on an ODS2 column through gradient elution at a flow rate of 1.0 ml·min −1 . The excitation and emission wavelengths were set at 340 and 455 nm, respectively. The mobile phase A was 100% methanol and the mobile phase B consisted of 30 mmol·L −1 sodium acetate (pH 6.8). The injection volume was 20 μl and the single run time was 45 min. Several parameters, accuracy, precision, and stability, were verified and the results showed the established method had good sensitivity and resolution for all of the 13 compounds and internal standard in mouse brain.
研究领域:
生物化学
·
医学研究
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分析化学
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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）