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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PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2026
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IF 3.2
Yuchen Zheng,Zijia Liu,Zijie Zhao,Chao Sheng,Wenzhuo Li,Duo Tang,Yunlu Ning,Renhang Zhou,Ao Li,Zhixiang Zhou
As an emerging contaminant, nanoplastics (NPs) are widespread in the food chain and environment, raising concerns about their potential toxicity. However, their effects on lipid metabolic homeostasis and the underlying mechanisms remain unclear. This study used polystyrene nanoplastics (PS-NPs), common in food packaging, to examine their impact on adipogenic differentiation and lipid synthesis. Our research results indicated that after 10 days of oral exposure, PS-NPs significantly accumulated in the adipose tissue of mice. Within the exposure concentration range of 1-100 μg/mL, PS-NPs significantly increased the expression of genes related to adipogenesis, accelerated mitotic clonal expansion (MCE) during early differentiation, and enhanced triglyceride (TG) accumulation in mouse 3T3-L1 preadipocytes, leading to adipogenic differentiation and lipogenesis. These effects were positively correlated with the exposure concentration. Protein quantification and immunofluorescence revealed that PS-NPs promoted the nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ). Molecular dynamics simulations confirmed that PS-NPs bind to the nuclear localization signal (NLS) region of PPARγ. These findings suggested a new molecular mechanism in which PS-NPs influence PPARγ′s subcellular localization through NPs-protein interactions, triggering adipogenic programs. This study provides valuable insights for the safety assessment and toxicology of nanoplastics.
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高影响因子
LIFE SCIENCES
·
2026
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IF 6.4
Zhiyu Xi,Wang Zhang,Qiang Liu,Qingyan Wang,Yinbao Qi
Background The ketogenic diet (KD) is an established therapy for drug-resistant epilepsy, yet its antiseizure mechanisms remain unclear. This study investigates whether KD modulates lipid metabolism-related genes to exert antiseizure effects in a mouse model of temporal lobe epilepsy. Methods Chronic epilepsy was induced in adult mice via systemic kainic acid (KA). Epileptic mice were fed either a standard chow diet (CD) or KD. Seizure activity was monitored via electroencephalography and behavioral scoring. Temporal lobe transcriptomic changes were analyzed using RNA sequencing. The role of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway was investigated in vivo and in primary hippocampal neurons using pharmacological agonists/antagonists and siRNA-mediated knockdown. Results KD-fed mice exhibited significantly reduced seizure frequency and severity compared to CD-fed controls. Transcriptomic analysis identified 41 differentially expressed lipid metabolism-related genes in the KD group. Perilipin 1 (Plin1) emerged as a top hub gene and was markedly upregulated in the hippocampus of KD-fed mice, associated with a significant increase in neuronal lipid droplet formation. In vitro, KD's effects were recapitulated by a PPARγ agonist and blocked by an antagonist, demonstrating that PPARγ mediates this transcriptional regulation. Knockdown of Plin1 in KA-treated neurons reduced lipid droplet formation and concurrently increased neuronal excitability (c-Fos expression), establishing a direct mechanistic link. Conclusion The ketogenic diet exerts antiseizure effects that may be related to activation of the PPARγ pathway, which upregulates Plin1 to promote lipid droplet formation in hippocampal neurons. This sequestration of fatty acids represents a novel mechanism for reducing neuronal excitability in chronic epilepsy.
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Advanced Science
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2026
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IF 14.1
Mingquan Gao,Xudong Yu,Ziqian Shang,Mengyao Tan,Xie Huang,Zaizhi Du,Xiaojiao Wang,Xinrui Yang,Ximei Luo,Weidong Wang,Rong Li,Shenglin Luo
Radiation‐induced lung injury (RILI) is a major complication of nuclear radiation exposure and thoracic radiotherapy, driven in part by a vicious cycle of oxidative stress and mitochondrial dysfunction. Peroxisome proliferator‐activated receptor gamma (PPAR‐γ), a key regulator of mitochondrial homeostasis and inflammatory resolution, therefore represents a potential therapeutic target, yet multi‐omics analyses revealed that this immunometabolic checkpoint remains functionally constrained in irradiated macrophages. To reactivate this pathway, we developed an inhalable, ROS‐responsive nanospray (HANP) by loading nicotinamide adenine dinucleotide (NAD + ) and astaxanthin (ASX) into a hollow mesoporous polydopamine (HMPDA) shell. Excess ROS in microenvironment triggers oxidative degradation of the HMPDA shell, enabling intracellular release of NAD + and ASX. Mechanistically, NAD + promotes SIRT1‐mediated deacetylation of PPAR‐γ, whereas ASX serves as an activating ligand, thereby cooperatively restoring PPAR‐γ signaling. This response re‐establishes macrophage mitochondrial homeostasis by coordinating mitochondrial biogenesis and mitophagy, which subsequently promotes a shift toward a reparative macrophage phenotype. In murine models of focal thoracic irradiation and lethal whole‐body irradiation, HANP markedly attenuated lung injury and improved survival. Collectively, these findings identify macrophage PPAR‐γ as a therapeutically actionable redox‐immunometabolic regulator and support inhaled dual‐activation of this pathway as a promising strategy for protection against RILI in both clinical and emergency settings. A nebulized nanoassembly alleviates radiation‐induced lung injury by reprogramming macrophages through coordinated ROS scavenging, NAD + replenishment, and PPAR‐γ activation. Redox balance, mitochondrial homeostasis, and immune regulation are restored, revealing a microenvironment‐centered strategy for localized radioprotection.
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FOOD AND CHEMICAL TOXICOLOGY
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2026
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IF 3.2
Yuxing Liao,Huiqing Liang,Hongmei Huang,Wenjie Yang,Shuangyan Su,Cuixiang Zhang,Yuxi Xiao,Jiaqi Gong,Qirong Yang,Guihua Wang,Guiyuan Chen,Xueying Li
PPARG identified as shared core target of DEHP and MEHP in HCC via network toxicology. • PPARG upregulation linked to poor overall survival in hepatocellular carcinoma. • DEHP/MEHP exposure induces lipid accumulation and PPARG expression in HepG2 cells. • Metabolomics reveals phthalate-induced disruptions in lipid and nucleotide pathways. Di(2-ethylhexyl) phthalate (DEHP) and its primary metabolite mono(2-ethylhexyl) phthalate (MEHP) have been implicated in metabolic dysregulation and carcinogenesis, but their potential links to hepatocellular carcinoma (HCC) remain unclear. Using network toxicology and pan-cancer analyses, we identified PPARG as a candidate shared target of DEHP and MEHP. PPARG was upregulated in HCC tissues, and higher expression was associated with poorer overall survival in the TCGA-LIHC cohort. Molecular docking and dynamics simulations predicted a more favorable and stable interaction between MEHP and PPARG than between DEHP and PPARG. In HepG2 cells, both compounds increased lipid accumulation and PPARG expression. Rosiglitazone promoted lipid accumulation and upregulated the lipid-storage genes DGAT2 and PLIN2, whereas GW9662 attenuated DEHP/MEHP-induced lipid accumulation and related transcriptional responses. Untargeted LC–MS metabolomics revealed relative alterations in phosphatidylcholine and phosphatidylethanolamine features and suggested perturbations in fatty acid-, bile acid-, arachidonic acid-, and nucleotide-related pathways. Collectively, these findings support a functional contribution of PPARG to DEHP/MEHP-associated lipid accumulation, potentially involving a DGAT2/PLIN2-related lipid-storage program, and provide mechanistic clues to phthalate-associated metabolic dysregulation in liver cancer cells. Download: Download high-res image (364KB) Download: Download full-size image
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ENVIRONMENTAL POLLUTION
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2025
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IF 7.3
Yingying Yu,Kuankuan Yuan,Difei Tong,Weixia Zhang,Weishang Zhou,Weifeng Li,Wei Shi,Weidong Yang,Xinguo Zhao,Guangxu Liu
Invertebrates constitute the largest group of animals on Earth, accounting for approximately 97 % of all animal species. Although the heart of invertebrates could be a sensitive target for environmental pollution, potential cardiotoxicity for most contaminants has received little attention. In this study, perfluorooctanoic acid (PFOA) and thick-shell mussels ( Mytilus coruscus ) were used to investigate the effect of PFOA on cardiac performance and the potential underlying mechanisms. Heart beat monitoring demonstrated that four-week exposure to 0.5 and 5.0 μg/L of PFOA resulted in bradycardia and arrhythmia in thick-shell mussels. Moreover, considerably more triglyceride (TG) accumulation, higher lipoprotein lipase (LPL) and lipase (LPS) activities, and disruption of lipid metabolism-related genes were observed in the hearts of PFOA-exposed mussels. In addition, comparable adverse impacts were detected in mussels treated with proliferator-activated receptor gamma (PPARγ) agonist whereas the PFOA-induced effects were fully or partially alleviated by PPARγ antagonist. Furthermore, molecular docking and molecular dynamics simulation revealed a high binding affinity of PFOA to the PPARγ of 12 invertebrates, including thick-shell mussels. In general, our data suggest that PFOA may pose a severe threat to cardiac performance of invertebrate species by inserting into the binding pocket of PPARγ, and thereby causing cardiac lipid metabolism disorders.
研究领域:
环境科学
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毒理学
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分子生物学
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PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2019
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IF 7.149
Wei Guo,Jian Han,Shengmin Wu,Xiongjie Shi,Qiangwei Wang,Bingsheng Zhou
Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is a ubiquitous environmental contaminant, but its toxicity is not fully understood. Accordingly, we investigated the effects of TBPH and its metabolite, mono-(2-ethyhexyl)tetrabromophthalate (TBMEHP), on lipid metabolism using a zebrafish model. The molecular docking study revealed that TBPH and TBMEHP bind to zebrafish peroxisome proliferator-activated receptor γ (PPARγ), with binding energies similar to rosiglitazone, a PPARγ agonist. Zebrafish embryos 0.75 hpf were exposed to TBPH (0.2–2000 nM) or TBMEHP (0.2–2000 nM) until 72 hpf, and their effects on PPARγ-mediated lipid metabolism were evaluated. Significant regional DNA demethylation of the PPARγ promoter was observed in the larvae at 72 hpf. Demethylation of the PPARγ promoter accompanied by upregulation of tet1 and tet2 transcription caused upregulation of PPARγ transcription and certain downstream genes involved in lipid lipolysis, transport, and metabolism. The triglyceride and total cholesterol concentrations in the larvae were significantly reduced following exposure to TBPH or TBMEHP. Furthermore, significant increases in the whole ATP content and locomotor activity in the 120 hpf larvae were observed. The overall results suggest that both TBPH and TBMEHP affect methylation of the PPARγ promoter, subsequently influencing larvae lipid metabolism via the PPARγ signaling pathway and disrupting energy homeostasis.
研究领域:
环境毒理学
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分子生物学
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发育生物学
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表观遗传学
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Research
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2025
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IF 10.7
Ningning He,Mengjie Mu,Xiaofang Li,Qingyuan Hao,Kaiwei Chen,Xinnan Zhao,Yang Sun,Haoyu Wang,Zhinan Wu,Hewei Liang,Mengmeng Wang,Liang Xiao,Tao Yu,Zhi-Peng Wang,Jixing Peng,Yuanqiang Zou,Shangyong Li
Antibiotic cocktails (ABX) serve as potent therapeutic interventions for refractory ulcerative colitis (UC), yet invariably induce gut dysbiosis. This study demonstrates that pectin oligosaccharides synergistically enhance ABX efficacy by restoring gut microbiota balance and selectively enriched antibiotic-resistant Parabacteroides goldsteinii in a colitis mouse model. Our results further indicate that the gavage administration of P. goldsteinii AM58-2XD markedly alleviated colitis via enhancing the branched-chain amino acid metabolic pathway, particularly by facilitating valine metabolism. Notably, these anticolitis effects were partially attenuated in P. goldsteinii ΔilvE mutants, which are defective in valine-derived isobutyrate (IBN) biosynthesis. We further demonstrated that exogenous IBN supplementation effectively alleviated colitis symptoms in mice and enhanced gut barrier function via activation of the peroxisome proliferator-activated receptor γ (PPARγ) pathway. Conditional knockout of PPARγ in Caco-2 intestinal epithelial cells markedly abrogated the IBN-induced enhancement of tight junctions, thereby substantiating the critical role of the IBN-PPARγ pathway in metabolite-mediated mucosal repair. Collectively, we delineate a prebiotic/probiotic–metabolite axis wherein P. goldsteinii facilitates mucosal repair via IBN/PPARγ-dependent epithelial metabolic reprogramming. This insight redefines antibiotic-resistant commensals as precise biotherapeutics for microbiota restoration in refractory UC management.
研究领域:
微生物组学
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炎症性肠病
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代谢生物学
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黏膜免疫
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转化医学
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肠道微生态
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高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2020
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IF 4.545
Zhishen Xie,Jianping Zhao,Hui Wang,Yali Jiang,Qiaoling Yang,Yu Fu,Huahui Zeng,Christian Hölscher,Jiangyan Xu,Zhenqiang Zhang
This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (Aβ) and the possible mechanisms involved. MG dose-dependently reduces Aβ deposition, toxicity and memory impairment caused by Aβ in transgenic C. elegans . More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist. MG is more effective in enhancing PPAR-γ luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR-γ (PPAR-γ-LBD). As expected, MG inhibited the luciferase activity of NF-κB and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased Aβ-induced reactive oxygen species (ROS). The target gene LXR of PPAR-γ is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of Aβ, and these effects were also reversed by GW9662. In summary, MG can attenuate Aβ-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of Aβ, which is dependent on PPAR-γ.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
Journal of Advanced Research
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2021
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IF 10.479
Zhenxing Liang,Ying Chen,Zheng Wang,Xue Wu,Chao Deng,Changyu Wang,Wenwen Yang,Ye Tian,Shaofei Zhang,Chenxi Lu,Yang Yang
Introduction Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers. Objectives The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms. Methods ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling. Results PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1. Conclusion In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy.
研究领域:
药理学
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心脏病学
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肿瘤学
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细胞生物学
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分子生物学
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高影响因子
BRAIN RESEARCH BULLETIN
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2023
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IF 3.8
Yushuang Liu,Hanshu Zhao,Nan Chen,Yuelong Li,Zeyang Zheng,Zhiyu Sun,Zhongling Zhang
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress occur in ischemic stroke. The disruption of these two organelles can directly lead to cell death through various signaling pathways. Thus, investigation of the associated molecular mechanisms in cerebral ischemia is a prerequisite for stroke treatment. Pleckstrin homology-like domain family A member 1 (PHLDA1) is a multifunctional protein that can modulate mitochondrial function and ER stress in cardiomyocyte and cancer cells. This work studied the role of PHLDA1 in cerebral ischemic/reperfusion (I/R) injury and explored the underlying mechanisms associated with mitochondrial functions and ER stress. Middle cerebral artery occlusion/reperfusion (MCAO/R)-treated mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated neurons were used as I/R models in vivo and in vitro, respectively. PHLDA1 was upregulated in ischemic penumbra of MCAO/R-induced mice and OGD/R-exposed neurons. In vitro , PHLDA1 knockdown protected neurons from OGD/R-induced apoptosis. In vivo , PHLDA1 silencing facilitated functional recovery and reduced cerebral infarct volume. Mechanistically, PHLDA1 knockdown promoted PPARγ nuclear translocation, which may mediate the effects on reversion of mitochondrial functions and alleviation of ER stress. In summary, PHLDA1 knockdown alleviates neuronal ischemic injuries in mice. PPARγ activation and mitochondrial dysfunction and endoplasmic reticulum stress attenuation are involved in the underlying mechanisms.
研究领域:
神经科学
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分子生物学
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细胞生物学
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药理学
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高影响因子
Microbiome
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2023
·Vol. 11
·期 1
·1-20
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IF 15.5
Sun Penghao,Wang Mengli,Liu Yong-Xin,Li Luqi,Chai Xuejun,Zheng Wei,Chen Shulin,Zhu Xiaoyan,Zhao Shanting
Background Aberrant tryptophan (Trp)-kynurenine (Kyn) metabolism has been implicated in the pathogenesis of human disease. In particular, populations with long-term western-style diets are characterized by an excess of Kyn in the plasma. Host-gut microbiota interactions are dominated by diet and are essential for maintaining host metabolic homeostasis. However, the role of western diet-disturbed gut microbiota-colonocyte interactions in Trp metabolism remains to be elucidated. Results Here, 4-week-old mice were fed with a high-fat diet (HFD), representing a typical western diet, for 4 weeks, and multi-omics approaches were adopted to determine the mechanism by which HFD disrupted gut microbiota-colonocyte interplay causing serum Trp-Kyn metabolism dysfunction. Our results showed that colonocyte-microbiota interactions dominated the peripheral Kyn pathway in HFD mice. Mechanistically, persistent HFD-impaired mitochondrial bioenergetics increased colonic epithelial oxygenation and caused metabolic reprogramming in colonites to support the expansion of Proteobacteria in the colon lumen. Phylum Proteobacteria -derived lipopolysaccharide (LPS) stimulated colonic immune responses to upregulate the indoleamine 2,3-dioxygenase 1 (IDO1)-mediated Kyn pathway, leading to Trp depletion and Kyn accumulation in the circulation, which was further confirmed by transplantation of Escherichia coli ( E.coli ) indicator strains and colonic IDO1 depletion. Butyrate supplementation promoted mitochondrial functions in colonocytes to remodel the gut microbiota in HFD mice, consequently ameliorating serum Kyn accumulation. Conclusions Our results highlighted that HFD disrupted the peripheral Kyn pathway in a gut microbiota-dependent manner and that the continuous homeostasis of gut bacteria-colonocytes interplay played a central role in the regulation of host peripheral Trp metabolism. Meanwhile, this study provided new insights into therapies against western diet-related metabolic disorders.
Video Abstract
研究领域:
营养学
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微生物学
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代谢学
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免疫学
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胃肠病学
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高影响因子
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