Toxins
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2021
·Vol. 13
·期 11
·802
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IF 4.546
Qian-Wen Zheng,Xu-Fen Ding,Hui-Jun Cao,Qian-Zhi Ni,Bing Zhu,Ning Ma,Feng-Kun Zhang,Yi-Kang Wang,Sheng Xu,Tian-Wei Chen,Ji Xia,Xiao-Song Qiu,Dian-Zhen Yu,Dong Xie,Jing-Jing Li
Ochratoxin A(OTA) is considered to be one of the most important contaminants of food and feed worldwide. The liver is one of key target organs for OTA to exert its toxic effects. Due to current lifestyle and diet, nonalcoholic fatty liver disease (NAFLD) has been the most common liver disease. To examine the potential effect of OTA on hepatic lipid metabolism and NAFLD, C57BL/6 male mice received 1 mg/kg OTA by gavage daily. Compared with controls, OTA increased lipid deposition and TG accumulation in mouse livers. In vitro OTA treatment also promoted lipid droplets accumulation in primary hepatocytes and HepG2 cells. Mechanistically, OTA prevented PPARγ degradation by reducing the interaction between PPARγ and its E3 ligase SIAH2, which led to activation of PPARγ signaling pathway. Furthermore, downregulation or inhibition of CD36, a known of PPARγ, alleviated OTA-induced lipid droplets deposition and TG accumulation. Therefore, OTA induces hepatic steatosis via PPARγ-CD36 axis, suggesting that OTA has an impact on liver lipid metabolism and may contribute to the development of metabolic diseases.Keywords:fatty liver disease;lipid metabolism;OTA;PPARKey Contribution:The in vitro and in vivo study reveal that OTA induces hepatic steatosis via PPARγ-CD36 axis. OTA prevents PPARγ from ubiquitination-mediated degradation by reducing the expression of the E3 ligase SIAH2 and SIAH2-PPARγ interaction.
研究领域:
毒理学
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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
Nutrients
·
2022
·Vol. 14
·期 12
·2411
·
IF 6.706
Zhuohui Zhao,Zhen-Tao Deng,Suling Huang,Mengmeng Ning,Ying Feng,Yu Shen,Qin-Shi Zhao,Ying Leng
Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease worldwide, with no effective therapies available. Discovering lead compounds from herb medicine might be a valuable strategy for the treatment of NASH. Here, we discovered Alisol B, a natural compound isolated fromAlisma orientalis(Sam.), that attenuated hepatic steatosis, inflammation, and fibrosis in high-fat diet plus carbon tetrachloride (DIO+CCl4)-induced and choline-deficient and amino acid-defined (CDA)-diet-induced NASH mice. RNA-seq showed Alisol B significantly suppressed CD36 expression and regulated retinol metabolism in NASH mice. In mouse primary hepatocytes, Alisol B decreased palmitate-induced lipid accumulation and lipotoxicity, which were dependent on CD36 suppression. Further study revealed that Alisol B enhanced the gene expression of RARα with no direct RARα agonistic activity. The upregulation of RARα by Alisol B reduced HNF4α and PPARγ expression and further decreased CD36 expression. This effect was fully abrogated after RARα knockdown, suggesting Alisol B suppressed CD36 via regulating RARα-HNF4α-PPARγ cascade. Moreover, the hepatic gene expression of RARα was obviously decreased in murine NASH models, whereas Alisol B significantly increased RARα expression and decreased CD36 expression, along with the downregulation of HNF4α and PPARγ. Therefore, this study showed the unrecognized therapeutic effects of Alisol B against NASH with a novel mechanism by regulating RARα-PPARγ-CD36 cascade and highlighted Alisol B as a promising lead compound for the treatment of NASH.Keywords:Alisol B;non-alcoholic steatohepatitis;RARα;CD36
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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PubMed
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Shiwen Wang,Ying Shen,Binbin Hu,Qiping Wu,Nanzhou Wang,Zichao Wang,Zifeng Zhang,Yujie Li,Jianhui Jiang
Breast cancer therapy confronts dual challenges of metabolic plasticity-driven drug resistance and immunosuppression. To address this, we developed DCP-TPP, a therapeutic nanoplatform that integrates dysregulation of copper homeostasis and lipid metabolism for precise breast cancer therapy. Leveraging the overexpression of cluster of differentiation 36 (CD36) in breast cancer cells, DCP-TPP employs fatty acid camouflage (PCM) to deliver disulfiram (DSF) and photothermal Cu3BiS3 to cancer cells and features triphenylphosphonium (TPP) modification for targeted mitochondrial drug delivery. Near-infrared (NIR) irradiation triggers the phase transition of DCP-TPP’s outer layer, inducing spatiotemporal release of DSF to liberate copper ions from inert Cu3BiS3, thereby generating diethyldithiocarbamate–copper complex (CuET). This disrupts copper homeostasis and induces cuproptosis, which subsequently triggers S-acetyltransferase (DLAT) aggregation, impairing tricarboxylic acid (TCA) cycle flux, acetyl-CoA production, ATP citrate lyase (Acly)-dependent lipogenesis, and ultimately collapses mitochondrial oxidative phosphorylation. Multiomics profiling revealed oleic acid depletion, arachidonic acid oxidation, and glutathione exhaustion, collectively amplifying metabolic collapse. DCP-TPP-induced cell death enhanced dendritic cell (DC) activation and CD8+ T cell infiltration. In breast cancer models, DCP-TPP achieved 90.9% tumor suppression, with 60% of mice resisting rechallenge. By transforming lipid metabolic dependency into a therapeutic vulnerability and coupling it with copper ion toxicity, DCP-TPP offers a promising strategy for breast cancer therapy.
研究领域:
癌症生物学
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纳米医学
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免疫治疗
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代谢工程
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生物无机化学
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靶向药物递送
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2022
·Vol. 179
·期 17
·4440-4456
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IF 9.473
Mengru Bai,Mingyang Chen,Qingquan Zeng,Shuanghui Lu,Ping Li,Zhiyuan Ma,Nengming Lin,Caihong Zheng,Hui Zhou,Su Zeng,Dongli Sun,Huidi Jiang
Background and Purpose Plasma triglyceride (TG) levels increase as gestation proceeds, and abnormal elevation of TG increases the risk of pregnancy complications. The current study explored the mechanisms involved in hypertriglyceridaemia during pregnancy. Experimental Approach Lipid profile and expression levels of key genes involved in liver TG metabolism in non-pregnant and pregnant mice were studied. The effects of pregnancy-related hormones on key genes and the underlying mechanisms were uncovered in vitro and in vivo. Key Results Plasma and hepatic TG levels were elevated, while hepatic fatty acid translocase (FAT/CD36) was up-regulated in pregnant mice. Corticosterone and cortisol (endogenous glucocorticoids that are elevated during pregnancy), but not oestradiol or progesterone, significantly up-regulated CD36 in hepatocytes, and this was abolished after knockdown of the glucocorticoid receptor (GR) using a siRNA or in the presence of GR antagonists, RU486 and AL082D06. The luciferase reporter gene and chromatin immunoprecipitation assay further revealed that corticosterone/cortisol promoted the direct binding of GR to the CD36 promoter and up-regulated its transcription. Chronic corticosterone exposure induced liver lipid accumulation and increased plasma TG levels in mice, which were attenuated by RU486 via inhibition of the GR-CD36 pathway. Conclusions and Implications Increased corticosterone/cortisol induces liver lipid accumulation and hypertriglyceridaemia during pregnancy by accelerating fatty acid uptake into hepatocytes via activation of GR and its target gene, CD36. Our results may be useful for the prevention of severe hypertriglyceridaemia and associated pregnancy complications. Graphical
研究领域:
内分泌学
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肝病学
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药理学
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PubMed
高影响因子
TOXICOLOGY LETTERS
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2022
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IF 4.271
Mingyang Chen,Mengru Bai,Yaodong Yi,Shuanghui Lu,Jun Luo,Ping Li,Hengbin Zhang,Huidi Jiang,Hui Zhou
Glucocorticoids such as dexamethasone (DEX) are widely prescribed to treat numerous conditions and diseases. However, glucocorticoid-induced liver lipid metabolism disorder, even nonalcoholic fatty liver disease , has caused extensive attention. Since fatty acid transporters such as CD36 and FATP play crucial roles in hepatic fatty acid uptake, this work examined their potential involvement in DEX-induced liver lipid accumulation. Chronic DEX administration (1–5 mg/kg/day over 28 days) induced hepatic lipid accumulation in mice. Fatty acid uptake in HepG2 cells and mouse primary hepatocytes was also stimulated after incubation with 0.5–2 μM DEX. Meanwhile, qPCR and western blotting demonstrated dose-dependent upregulation of CD36 expression by DEX in the mouse liver and in cultured hepatocytes. Glucocorticoid receptor (GR) inhibition with mifepristone (RU486) and siRNA-mediated GR knockdown attenuated lipid accumulation in hepatocytes by inhibiting DEX-induced CD36 upregulation, and direct binding of GR to the CD36 promoter was demonstrated by luciferase reporter and chromatin immunoprecipitation assays. These results indicate that DEX promotes free fatty acid uptake leading to hepatic steatosis by upregulating CD36 expression via activation of GR. Thus, strategies aimed at inhibiting GR/CD36 expression or activity might help prevent or reduce the onset and progression of hepatic lipid metabolism disorders induced by glucocorticoid drugs.
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
ANTIOXIDANTS & REDOX SIGNALING
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2025
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IF 6.1
Wenhui Yan,Xin Cui,Tingli Guo,Na Liu,Zhuanzhuan Wang,Yuzhuo Sun,Yuanrui Shang,Jieyun Liu,Yuanyuan Zhu,Yangyang Zhang,Lina Chen
Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide. Arachidonic acid 15-lipoxygenase (ALOX15), an enzyme catalyzing the peroxidation of polyunsaturated fatty acids, plays a crucial role in various diseases. Here, we sought to investigate the involvement of ALOX15 in MASLD.Results: In this study, we observed upregulation of ALOX15 in the liver of high-fat diet (HFD)- and streptozotocin (STZ)-induced mice. Metabolomic analysis revealed elevated levels of ALOX15 metabolites, 12(S)-hydroperoxyeicosatetraenoic acid and 15(S)-hydroperoxyeicosatetraenoic acid. Transcriptomic analysis showed that the increased fatty acid uptake regulated by the PPARγ/CD36 pathway predominated in lipid accumulation. To elucidate the mechanism underlying ALOX15-induced lipid accumulation, HepG2 cells were transfected with a lentivirus expressing ALOX15 or small interfering RNA targeting ALOX15 and exposed to palmitic acid (PA). Both ALOX15 overexpression and PA exposure led to increased intracellular free fatty acid and triglyceride, resulting in lipotoxicity. ALOX15 overexpression aggravated the effect of PA, while the knockdown of ALOX15 attenuated PA-induced lipotoxicity. Moreover, the treatment with PPARγ antagonist GW9662 or CD36 inhibitor sulfosuccinimidyl oleate sodium effectively reduced lipid accumulation and lipotoxicity resulting from ALOX15 overexpression and PA exposure, indicating the involvement of the PPARγ/CD36 pathway in ALOX15-mediated lipid accumulation. Furthermore, liraglutide, a widely used glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA), improved hepatic lipid accumulation in HFD/STZ-induced mice by suppressing the ALOX15/PPARγ/CD36 pathway.Innovation and Conclusion: Our study underscores the potential of ALOX15 as an emerging therapeutic target for MASLD. In addition, the GLP-1RA may confer hepatoprotection by regulating ALOX15, enhancing our comprehension of the mechanisms underpinning their protection on MASLD. Antioxid. Redox Signal. 00, 000–000.
研究领域:
肝病学
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内分泌学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2024
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IF 7.1
Chaojuan Wen,Xinyue Yu,Jingya Zhu,Jingshu Zeng,Xielan Kuang,Youao Zhang,Shiyu Tang,Qingjiong Zhang,Jianhua Yan,Huangxuan Shen
Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly, is primarily characterized by the degeneration of the retinal pigment epithelium (RPE). However, effective therapeutic options for dry AMD are currently lacking, necessitating further exploration into preventive and pharmaceutical interventions. This study aimed to investigate the protective effects of gastrodin on RPE cells exposed to oxidative stress. We constructed an in vitro oxidative stress model of 4-hydroxynonenal (4-HNE) and performed RNA-seq, and demonstrated the protective effect of gastrodin through mouse experiments. Our findings reveal that gastrodin can inhibit 4-HNE-induced oxidative stress, effectively improving the mitochondrial and lysosomal dysfunction of RPE cells. We further elucidated that gastrodin promotes autophagy and phagocytosis through activating the PPARα-TFEB/CD36 signaling pathway. Interestingly, these outcomes were corroborated in a mouse model, in which gastrodin maintained retinal integrity and reduced RPE disorganization and degeneration under oxidative stress. The accumulation of LC3B and SQSTM1 in mouse RPE-choroid was also reduced. Moreover, activating PPARα and downstream pathways to restore autophagy and phagocytosis, thereby countering RPE injury from oxidative stress. In conclusion, this study demonstrated that gastrodin maintains the normal function of RPE cells by reducing oxidative stress, enhancing their phagocytic function, and restoring the level of autophagic flow. These findings suggest that gastrodin is a novel formulation with potential applications in the development of AMD disease.
研究领域:
眼科学
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药理学
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细胞生物学
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分子生物学
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神经科学
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DOI
PubMed
高影响因子
Research
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2025
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IF 10.7
Di Yang,Lianhui Li,Kailai Zang,Wanyong Ma,Yuling Yang,Yani Sun,Bingqiang Zhang,Zunshuang Gong,Mingkang Yu,Qiyuan Du,Xiaokun Liu,Zhe Wang,Qiyue Xu,Ning Li
Hepatic lipid dysregulation drives metabolic dysfunction-associated steatotic liver disease (MASLD); nonetheless, the precise regulatory mechanisms remain incompletely elucidated. In this study, we examine the function of EVA1A, a known hepatocellular carcinoma tumor suppressor, in hepatic lipid metabolism. Hepatic EVA1A was markedly down-regulated in individuals diagnosed with MASLD, as well as in mice subjected to a high-fat diet. Hepatocyte-specific knockout of Eva1a in mice resulted in significant hepatic steatosis, accompanied by disrupted fatty acid metabolism, marked by increased fatty acid uptake and compromised β-oxidation, while hepatic Eva1a overexpression reversed these metabolic changes and largely alleviated fatty liver in ob/ob mice. Mechanistically, EVA1A deficiency activates mTORC1 (mechanistic target of rapamycin complex 1)–PPARγ2 (peroxisome proliferator-activated receptor γ2) signaling to up-regulate CD36 transcription. Concurrently, it transcriptionally represses the S-depalmitoylase APT1 while enhancing palmitoyl acyltransferases ZDHHC4/5, boosting CD36 palmitoylation. This dual action promotes CD36 plasma membrane localization for fatty acid uptake, reducing its mitochondrial distribution and impairing β-oxidation. Collectively, these results establish EVA1A as an essential regulator of hepatic lipid homeostasis, coordinating fatty acid uptake and β-oxidation by modulating CD36 expression and palmitoylation. Therefore, targeting the EVA1A–CD36 axis represents a promising therapeutic strategy for MASLD.
研究领域:
分子生物学
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代谢学
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肝病学
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细胞信号转导
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脂质研究
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产品关联
DOI
PubMed
高影响因子
CANCER LETTERS
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2026
·
IF 11.8
Xiaojuan Huang,Leina Ma,Yangyang Lu,Jinfeng Cui,Weiwei Qi,Jialin Song,Jing Guo,Shasha Wang,Jing Fang,Zhimin Lu,Wensheng Qiu
The efficacy of tyrosine kinase inhibitor (TKI)-based systemic therapy in advanced hepatocellular carcinoma (HCC) is often limited by drug resistance, the mechanisms of which remain incompletely understood. Here, we demonstrate that CD276, an immune checkpoint protein, promotes TKI resistance in HCC by reprogramming lipid metabolism. Upon TKI treatment, CD276 binds pSTAT3 and undergoes importin α/β-dependent nuclear translocation. In the nucleus, CD276 cooperates with STAT3 to promote CD36 transcription, thereby potentiating fatty acid uptake, lipid droplet accumulation, and mitochondrial fatty acid β-oxidation. This metabolic rewiring drives HCC proliferation and confers TKI resistance. Importantly, pharmacological inhibition of CD36 with sulfosuccinimidyl oleate sodium suppresses fatty acid uptake and tumor lipid metabolism, resensitizing resistant HCC cells to TKIs. Our findings reveal the CD276-STAT3-CD36 axis as a key regulator of lipid metabolic reprogramming in TKI resistance, providing a promising therapeutic target to overcome treatment resistance in HCC.
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Huijuan Luo,Nan Xu,Jiazhen Wu,Yuxuan Gan,Liping Chen,Fengkun Guan,Mengyao Li,Yucui Li,Jiannan Chen,Ziren Su,Yuhong Liu
Non-alcoholic steatohepatitis (NASH), an extreme progressive subtype of metabolic associated fatty liver disease, is well characterized by hepatic steatosis, injury and inflammation. It causes irreversible hepatic damage and there are no approved interventions for it. β-PAE, a representatively pharmacological active substance isolated from Pogostemon cablin , has been indicated to alleviate hepatic steatosis and injury through modulating lipid metabolism in rats with simple steatosis. However, its protection against NASH remains unclear. Here, this study explored the potential effect of β-PAE against high-fat diet-induced NASH in rats. The results displayed that β-PAE significantly reduced the gains of body weight and epididymal adipose tissue, liver index and attenuated liver histological damages in NASH rats. It also markedly alleviated hepatic inflammation by inhibiting NLRP3 inflammasome activation. In NASH, the active NLRP3 inflammasome is caused by hepatic lipid abnormal accumulation-induced oxidative stress. Excessive oxidative stress results in hepatic histanoxia, which exacerbates lipid metabolism disorders by elevating CD36 to suppress AMPK signalling pathways. Moreover, the lipid accumulation led by lipid metabolism dysfunction intensifies oxidative stress. A vicious circle is formed among oxidative stress, histanoxia and lipid accumulation, eventually, but β-PAE effectively interrupted it. Interestingly, soluble CD36 (sCD36) was tightly associated not only with hepatic steatosis and injury but also with inflammation. Collectively, β-PAE exerted a positive effect against NASH by interrupting the vicious circle among oxidative stress, histanoxia and lipid accumulation, and sCD36 may be a promising non-invasive tool for NASH diagnosis.
研究领域:
药理学
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肝病学
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代谢性疾病
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产品关联
DOI
PubMed
高影响因子
Small
·
2026
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IF 11.8
Liang Zhang,Mengxin He,Yao Lu,Shuai Lu,Jianmin Ding,Hong Ji,Jun Kang,CongHui Han,Jun Yan
Obesity-driven lipid accumulation in hepatocellular carcinoma (HCC) establishes a coupled metabolic-immunosuppressive niche that fuels tumor progression and undermines anti-tumor immunity. Through multiplexed immunofluorescence profiling of clinical HCC tissues stratified by visceral adiposity, we explicitly map this lipid-immunosuppressive landscape and demonstrate that fatty acid translocase CD36 overexpression directly correlates with FoxP3 + Treg infiltration and CD8 + T cell exclusion, defining a clinically actionable immunometabolic vulnerability. To therapeutically exploit this vulnerability, we engineer an AI-designed, structure-guided CD36-occluding nanoplatform (LAIBP) with intrinsic ultrasound-responsive sonodynamic capability. Mechanistically, LAIBP selectively blockades CD36-mediated exogenous lipid influx to impose metabolic vulnerability; subsequent ultrasound activation triggers a spatiotemporally controlled oxidative burst, driving disulfidoptosis-like cell death through NADPH depletion, redox imbalance, and cytoskeletal collapse in the lipid-replete tumor microenvironment. Transcriptomic analysis and protein-level validation indicate coordinated metabolic, redox, and immune-associated changes, with G protein-coupled receptor (GPCR)-associated phosphatidylinositol 3-kinase (PI3K)/ serine/threonine-protein kinase (Akt)/ Serine/threonine-protein kinase mTOR signaling and the cystine/glutamate transporter (SLC7A11) - phospholipid hydroperoxide glutathione peroxidase(GPX4) axis emerging as pathways associated with the observed metabolic-redox response. In obesity-associated implanted HCC mouse models, LAIBP combined with ultrasound irradiation suppresses tumor growth, reduces intratumoral lipid accumulation, and is associated with remodeling of the tumor immune microenvironment. Collectively, this work supports a clinically grounded rationale and a nanotherapeutic framework for further immunometabolic investigation in obesity-associated HCC. Conclusion The LAIBP nanoplatform, via the integrated paradigm of “metabolic entry blockade + redox homeostasis disruption + exogenous trigger amplification”, induces metabolic collapse and disulfidoptosis-like damage in HCC cells and is associated with remodeling of the antitumor immune microenvironment. This work supports a candidate sonodynamic, immunometabolism-associated strategy for obesity-associated HCC.
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DOI
高影响因子
Frontiers in Immunology
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2026
·
IF 7
Xiaokun Shen,Haitao Cao,Fujie Li,Wenya Wang,Xingshu Qi,Yarui Zhou,Bo Li,Qingjie Fan,Tao Yang,Shinan Li
Liver fibrosis is a major global health challenge, and it is an independent risk factor for the development of hepatocellular carcinoma (HCC). Several methods have been explored to improve liver fibrosis progression, but effective preventive and therapeutic strategies remain limited. Natural killer (NK) cells can limit the activation of hepatic stellate cells (HSCs), but they have exhibited impaired antifibrotic properties in liver fibrosis, and the underlying mechanisms are not well understood. In this study, we found that CD36 was markedly upregulated in NK cells from mice with liver fibrosis. The CD36 expression was negatively correlated with activation markers of NK cells. The CD36- NK cells exhibited elevated cytotoxic cytokine production and enhanced antifibrotic activity against HSCs. The adoptive transfer of CD36- NK cells alleviated liver fibrosis progression. Mechanistically, CD36 induced reactive oxygen species (ROS) and lipid peroxidation. These consequently triggered ferroptosis in NK cells. The blockage of CD36 or inhibition of ferroptosis in NK cells effectively restored their antifibrotic properties against HSCs. In summary, our findings demonstrated that the antifibrotic properties of NK cells were regulated by CD36. These results provide evidence that targeting CD36 could restore NK cell function for liver fibrosis immunotherapy.
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DOI
高影响因子
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