CELL DEATH AND DIFFERENTIATION
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2024
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IF 13.7
Wu Yachen,Zheng Wenzhong,Xu Guofeng,Zhu Lijun,Li Zhiqiang,Chen Jincao,Wang Lianrong,Chen Shi
Sterol regulatory element binding transcription factors (SREBPs) play a crucial role in lipid homeostasis. They are processed and transported to the nucleus via COPII, where they induce the expression of lipogenic genes. COPII maintains the homeostasis of organelles and plays an essential role in the protein secretion pathways in eukaryotes. The formation of COPII begins at endoplasmic reticulum exit sites (ERES), and is regulated by SEC16A, which provides a platform for the assembly of COPII. However, there have been few studies on the changes in SEC16A protein levels. The repetitive expansion of the hexanucleotide sequence GGGGCC within the chromosome 9 open reading frame 72 (C9orf72) gene is a prevalent factor in the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we found that the absence of C9orf72 leads to a decrease in SEC16A protein levels, resulting in reduced localization of the guanine nucleotide exchange factor SEC12 at the ERES. Consequently, the small GTP binding protein SAR1 is unable to bind the endoplasmic reticulum normally, impairing the assembly of COPII. Ultimately, the disruption of SREBPs transport decreases de novo lipogenesis. These results suggest that C9orf72 acts as a novel role in regulating lipid homeostasis and may serve as a potential therapeutic target for obesity.
研究领域:
分子生物学
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脂质代谢
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神经退行性疾病
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DOI
PubMed
高影响因子
iScience
·
2025
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IF 4.1
Zizheng Liu,Huiming Jiang,Zhaofeng Zhang,Ruiyang Jiang,Rongliang Wang,Jiawei Li,Weitong Li,Guihua Tan,Yuxiang Fei,Zhongyang Lv,Hu Guo,Ziyin Sun,Rui Wu,Hongfei Shi,Dongquan Shi
Chondrocytes experience adverse lipid metabolism disorders during the degeneration of cartilage in osteoarthritis (OA), while the underlying mechanisms remain poorly understood. SESN2, a highly conserved stress-inducible protein, plays a crucial role in regulating lipid metabolism. This study aims to investigate the role of SESN2 in the regulation of fatty acid metabolism in chondrocytes and elucidate the underlying molecular mechanisms in OA. The expression of SESN2 was significantly decreased in OA-affected human cartilage, and this decrease correlated with the upregulation of lipogenic enzymes. Sesn2 inhibited lipogenic enzyme expression in chondrocytes and improved cartilage homeostasis. Mechanistically, SESN2 inhibited the expression of SREBP1 and interacted with SCAP to deactivate SREBP1-mediated transcription for lipogenesis. Finally, overexpression of Sesn2 in mice undergoing DMM surgery ameliorated OA pathological manifestations and improved behavioral experiments performance through inhibiting fatty acid synthesis. Our findings revealed that SESN2 suppresses SREBP1-mediated transcription for lipogenic enzyme in chondrocytes and ameliorates OA progression. These results highlighted that targeting SESN2 may serve as a promising therapeutic strategy for OA.
研究领域:
分子生物学
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生物化学
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细胞生物学
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骨科
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医学研究
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DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
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2024
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IF 3
Junyi Jin,Yihui Wang,Yaoyuan Hu
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. STAM binding protein-like 1 (STAMBPL1), a key member of the COP9 signalosome subunit 5/serine protease 27/proteasome 26S subunit non-ATPase 7 (JAMM) family, is closely associated with tumor development. In this work, data from GSE101728 and GSE84402 chips were analyzed, and STAMBPL1 was selected as the target factor. This study aimed to reveal the potential function of STAMBPL1 in HCC. Clinical results showed that STAMBPL1 was significantly increased in tumor tissues of HCC patients, and its expression was strongly associated with tumor size and TNM stage. Furthermore, STAMBPL1-overexpressed Hep3B2.1-7 cell line or STAMBPL1-silenced SNU-182 cell line were established using lentivirus carrying cDNA encoding STAMBPL1 mRNA or shRNA targeting STAMBPL1, respectively. STAMBPL1-overexpressed cells exhibited a pronounced enhancement of proliferation in vitro and in vivo. Exogenous expression of STAMBPL1 increased the percentage of cells in the S phase and upregulated the expressions of CyclinD1 and Survivin. As expected, STAMBPL1 knockdown exhibited completely opposite effects, resulting in impaired tumorigenicity in vitro and in vivo. Mechanistically, STAMBPL1 activated Wnt/β-catenin pathway and increased the expression of downstream cancer-promoting genes. Interestingly, we found that STAMBPL1 was transcriptionally regulated by sterol regulatory element-binding protein 1 (SREBP1), a modulator of lipid metabolism, as evidenced by luciferase reporter and chromatin-immunoprecipitation (Ch-IP) assays. Notably, STAMBPL1 overexpression increased lipid accumulation in HCC cells and xenograft tumors. Totally our findings suggest that STAMBPL1 plays a vital role in the tumorigenicity of HCC cells. Modulation of Wnt/β-catenin and lipid metabolism may contribute to its pro-cancer effects. STAMBPL1 may serve as a therapeutic target of HCC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
HUMAN & EXPERIMENTAL TOXICOLOGY
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2022
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IF 3.247
Q Yang,Y Mao,J Wang,H Yu,X Zhang,X Pei,Z Duan,C Xiao,M Ma
Lipid metabolism is an important biochemical process in the body. Recent studies have found that environmental endocrine disruptors play an important role in the regulation of lipid metabolism. Bisphenol A (BPA), a common environmental endocrine disruptor, has adverse effects on lipid metabolism, but the mechanism is still unclear. This study aimed to investigate the effects of gestational BPA exposure on hepatic lipid metabolism and its possible mechanism in male offspring. The pregnant Sprague-Dawley rats were exposed to BPA (0, 0.05, 0.5, 5 mg/kg/day) from day 5 to day 19 of gestation to investigate the levels of triglyceride (TG) and total cholesterol (TC), and the expression of liver lipid metabolism-related genes in male offspring rats. The results showed that compared with the control group, the TG and TC levels in serum and liver in BPA-exposed groups was increased. And the expressions of liver fatty acid oxidation related genes, such as peroxisome proliferators-activated receptor α (PPARα) and carnitine palmitoyl transferase 1α (CPT1α), were down-regulated. However, the expressions of fatty acid synthesis related genes, such as sterol regulatory element binding proteins 1 (SREBP-1), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD-1), were up-regulated. The increased protein levels of mTOR and p-CRTC2 suggested that CREB-regulated transcription coactivator 2 (CRTC2) might be an important mediator in the mTOR/SREBP-1 pathway. In conclusion, these results demonstrated that mTOR/CRTC2/SREBP-1 could be affected by gestational BPA exposure, which may involve in the lipid metabolic disorders in later life.
研究领域:
环境健康
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内分泌学
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代谢
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2024
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IF 3.9
Chengping Kang,Qianqian Xiao,Xiaoxia Wang,Wanqian Guo,Haoran Zhang,Lilan Yuan,Zhe Zhao,Weidong Hao
Chlormequat chloride (CCC), a widely used plant growth regulator, is a choline analogue that has been shown to have endocrine-disrupting effects. Previous studies have shown that maternal exposure to CCC could induce hyperlipidemia and growth disruption in rat offspring. This study aims to further investigate the effects of peripubertal exposure to CCC on pubertal development and lipid homeostasis, as well as the underlying mechanisms. In vivo , male weanling rats were exposed to CCC (0, 20, 75 and 200 mg/kg bw/day) from post-natal day 21 to 60 via daily oral gavage. The results in rats showed that 75 mg/kg CCC treatment induced hepatic steatosis, predominantly microvesicular steatosis with a small amount of macrovesicular steatosis, in rat livers and 200 mg/kg CCC treatment induced liver damage including inflammatory infiltration, hepatic sinusoidal dilation and necrosis. In vitro , HepG2 cells were treated with CCC (0, 30, 60, 120, 240 and 480 μg/mL) for 24 h. And the results showed that CCC above 120 μg/mL induced an increase in triglyceride and neutral lipid levels of HepG2 cells. Mechanism exploration revealed that CCC treatment promoted the activation of mTOR/SREBP1 signalling pathway and inhibited activation of AMPK in both in vivo rat livers and in vitro HepG2 cells. Treatment with AMPK activator Acadesine (AICAR) could alleviate the lipid accumulation in HepG2 cells induced by CCC. Collectively, the present results indicate that CCC might induce hepatic steatosis by promoting mTOR/SREBP1 mediated lipogenesis via AMPK inhibition.
研究领域:
药理学
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毒理学
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内分泌学
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分子生物学
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细胞生物学
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PubMed
高影响因子
KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY
·
2024
·Vol. 28
·期 3
·219-227
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IF 1.6
Peiyu Lin,Xiyue Yang,Linghui Wang,Xin Zou,Lingli Mu,Cangcang Xu,Xiaoping Yang
Bladder cancer remains the 10th most common cancer worldwide. In recent years, metformin has been found to have potential anti-bladder cancer activity while high concentration of IC 50 at millimolar level is needed, which could not be reached by regular oral administration route. Thus, higher efficient agent is urgently demanded for clinically treating bladder cancer. Here, by conjugating artesunate to metformin, a novel artesunate-metformin dimer triazine derivative AM2 was designed and synthesized. The inhibitory effect of AM2 on bladder cancer cell line T24 and the mechanism underlying was determined. Anti-tumor activity of AM2 was assessed by MTT, cloning formation and wound healing assays. Decreasing effect of AM2 on lipogenesis was determined by oil red O staining. The protein expressions of Clusterin, SREBP1 and FASN in T24 cells were evaluated by Western blotting. The results show that AM2 significantly inhibited cell proliferation and migration at micromolar level, much higher than parental metformin. AM2 reduced lipogenesis and down-regulated the expressions of Clusterin, SREBP1 and FASN. These results suggest that AM2 inhibits the growth of bladder cancer cells T24 by inhibiting cellular lipogenesis associated with the Clusterin/SREBP1/FASN signaling pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
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IF 5.4
Yating Guo,Qiushuang Sun,Shijiao Wang,Mengdi Zhang,Yuanyuan Lei,Jiejie Wu,Xinhong Wang,Wenjun Hu,Haitao Meng,Zhiyu Li,Luzhou Xu,Fang Huang,Zhixia Qiu
Ethnopharmacological relevance Along with the gradually increasing incidence, nonalcoholic fatty liver disease (NAFLD) has already been influencing the health of more and more people in the world. Corydalis saxicola Bunting (CSB), a valuable folk medicine, is the dried whole grass of a perennial herb, Yanhuanglian ( Papaveraceae ), which has significant effects on various hepatitis, liver fibrosis , cirrhosis and other liver diseases. Corydalis saxicola Bunting total alkaloids (CSBTA), a mixture of alkaloids extracted from CSB, exhibit widely-accepted hepatoprotective effects. Aim of the study This study aimed to explore the therapeutic potential of CSBTA on NAFLD and the underlying mechanism. Materials and methods A mice model was established by high fat and high cholesterol diet (HFHCD) to study the benefits of CSBTA on the progression of NAFLD. The efficacy of CSBTA on NAFLD was revealed systematically via RNA-sequencing analysis. Further efficacy and molecular mechanism study were explored in mouse primary hepatocytes and HepG2 cells stimulated with high energy with or without pharmacological inhibition or gene silencing. Results CSBTA effectively improved the major hallmarks of NAFLD including liver lipid accumulation, liver injury, inflammation and fibrosis in HFHCD-fed mice. RNA sequencing and targeted qPCR analysis jointly evidenced CSBTA significantly suppressed the expression of Srebf1 , Acc1 and Fasn which are the genes responsible for fatty acid biosynthesis. Moreover, stable isotope tracer test denoted CSBTA reduced lipid accumulation via interrupting fatty acid biosynthesis in hepatocytes or the liver. Mechanistically, CSBTA could impede SREBP1 maturation via AMPK activation, thereby reducing DNL-derived lipid accumulation in hepatocytes. Conclusions CSBTA protected against hepatic steatosis and other hallmarks of NAFLD induced by HFHCD via suppressing DNL, through modulating the AMPK-SREBP1 axis. CSBTA may therefore have a therapeutic potential for NAFLD treatment.
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
TOXICOLOGY LETTERS
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2021
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IF 4.374
Shanqi Guo,Yangyi Zhang,Shuo Wang,Tong Yang,Baojie Ma,Xiaojiang Li,Yizhuo Zhang,Xingkang Jiang
Antimony is a common environmental contaminant that causes biological toxicity in exposed populations worldwide. Previous studies have revealed that antimony promotes prostate cancer growth by stabilizing the c-Myc protein and mimicking androgen activity. However, the role of lncRNAs in the regulation of antimony-induced carcinogenesis remains unknown, and the precise mechanisms need to be explored. In the present study, we found that chronic exposure to antimony promoted cell growth and lipid metabolic disequilibrium in prostate cancer. Mechanistically, we identified a long noncoding RNA molecule, PCA3, that was substantially upregulated in LNCaP cells in response to long-term antimony exposure. Functional studies indicated that abnormal PCA3 expression modulated antimony-induced proliferation and cellular triglyceride and cholesterol levels. In addition, PCA3 levels were found to be inversely correlated with MIR-132-3 P levels by acting as a decoy for MIR-132-3P. Besides, SREBP1 directly interacted with MIR-132-3 P to increase cell growth and disrupt lipid metabolism by targeting its 3’UTR regions. Taken together, our results revealed that lncRNA PCA3 promotes antimony-induced lipid metabolic disorder in prostate cancer by targeting MIR-132-3 P/SREBP1 signaling.
研究领域:
癌症生物学
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毒理学
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分子生物学
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环境健康
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Jue Liu,Yue-Xuan Liu,Yu-Song Song,Chen-Kai Liu,Fei-Xue Yu,Gao Liu,Tian-Rui Xu,Jun Sang
Ethnopharmacological relevance Paris polyphylla Smith var. yunnanensis (Franch.) Hand.-Mazz., known as “Chonglou” in traditional Chinese medicine, is clinically used in cancer therapy, with saponins identified as the key antitumor constituents. However, the therapeutic potential and mechanisms of the total saponins from P. polyphylla var. yunnanensis (PPT) against bladder cancer, particularly their ability to overcome chemoresistance, remain unexplored. Aim of the study This study aimed to investigate PPT's anti-bladder cancer effects and mechanisms, with a focus on its potential to overcome cisplatin resistance. Materials and methods We established a UPLC-DAD method for saponin profiling and developed an eco-friendly extraction protocol using hydroxypropyl- β -cyclodextrin-assisted extraction combined with macroporous resin purification to prepare PPT. Anti-cancer efficacy was assessed in bladder cancer cell lines, mouse/zebrafish xenograft models, and cisplatin-resistant models. Mechanistic investigations integrated network pharmacology, metabolomics, molecular docking, and experimental validations (siRNA silencing, western blotting, flow cytometry, molecular dynamics simulations, cellular thermal shift assay, and surface plasmon resonance). Results The hydroxypropyl- β -cyclodextrin-based extraction system enhanced PPT purity by 15-fold, with the purified fraction showing dose-dependent anti-bladder cancer activity in vitro and in vivo . Mechanistically, PPT exerted anti-proliferative, pro-apoptotic, anti-lipogenic, and chemosensitizing effects by inhibiting the growth factor receptor binding protein 2 (GRB2)-mediated Akt-SREBP1 signaling axis. Notably, polyphyllin VII, a key constituent of PPT, was identified as a novel GRB2 inhibitor, potently suppressing bladder cancer progression and overcoming cisplatin resistance. Conclusion This study demonstrates that targeting the GRB2-Akt-SREBP1 signaling axis is a promising strategy for bladder cancer therapy, further establishing PPT as a multicomponent phytomedicine and PPVII as a novel GRB2 inhibitor with high translational potential.
研究领域:
癌症研究
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药理学
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分子生物学
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民族药理学
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生物信息学
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信号转导
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2018
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IF 3.457
Li Zhang,Hui-Xia Li,Wu-Si Pan,Farhan Ullah Khan,Cheng Qian,Feng-Rong Qi-Li,Xiaojun Xu
Background and aims Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome and is characterized by steatosis, inflammation, and fibrosis. We aim to characterize the hepatoprotective effects of Leonurine hydrochloride (LH) and the possible pathway in a cell and rodent model of diet-induced steatohepatitis (NASH). Methods For in vitro studies, Palmitic acid (PA) and free fatty acid (FFA) induced HepG2 and HL7702 steatosis cell models were used. For in vivo studies, NASH was induced by feeding mice MCD diet. These mice received either placebo or LH at three different doses (50、100、200 mg/kg/day) for 6 weeks. Histological staining’s, and commercially available kits for ALT and AST and hepatic contents of TG, TC, MDA, SOD, and GSH were used to assess NASH. Furthermore, relative liver protein and gene expression levels were determined by Western Blot and qPCR, respectively. Results After establishing NASH models, LH treatment improved lipid accumulation, hepatic contents of TG, TC, and expression levels of ALT and AST in dose-dependent manner. Also, LH improved MDA, SOD, and GSH expression levels. The results of RT-PCR and Western blotting showed that LH upregulated the expression of AMPK phosphorylation and downregulated SREBP-1c and its target genes expression level. Conclusions Our data reveal the promising role of Leonurine hydrochloride in the prevention and treatment of NASH, in vitro and in vivo . This effect may be partially mediated by the AMPK/SREBP1 pathway. These findings provide a novel therapeutic target for the clinical treatment of NASH.
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
JOURNAL OF ETHNOPHARMACOLOGY
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2025
·
IF 5.4
Youyun Liu,Junxi Liu,Rui Xu,Yonglei Yuan,Qiwen Sun,Susu Ding,Feifei Wang,Liping Qu
Ethnopharmacological relevance Ludwigia adscendens (L.) Hara ( L. adscendens ) is a Traditional Chinese Medicine (TCM), first mentioned in Sheng Cao Yao Xing Bei Yao ( Essential Guide to Raw Herbal Properties ). It clears heat, removes dampness, detoxifies, and reduces swelling. In TCM, it is prescribed for acne caused by dampness-heat accumulation. It is also used for cold, fever, sore throat, boils, dermatitis, and snake or dog bites. Research shows it has antioxidant, antibacterial, anti-inflammatory, and anti-lipoxygenase effects. However, studies on its impact on sebaceous gland function (a key factor in acne pathogenesis) are still limited. Aim of the study This study aims to investigate the effects of L. adscendens extract (LHE) on sebaceous gland function and its mechanisms. Materials and methods Active compounds in LHE were identified using high-performance liquid chromatography (HPLC). Its effects on lipid synthesis, sebocyte proliferation, and reactive oxygen species (ROS) were assessed in a 5α-dihydrotestosterone (DHT)-induced sebocyte model. Untargeted lipidomics was used to analyse sebum composition and detect LHE-induced changes. Anti-inflammatory and antioxidant activities were evaluated using zebrafish models and biochemical assays. Sebum-regulatory efficacy was measured to assess LHE's impact on sebum production. Results LHE showed strong biological activity by activating the PPARγ/LXRα/SREBP1 pathway, reducing lipid production, inhibiting sebocyte hyperproliferation, and delivering notable antioxidant and anti-inflammatory effects. Lipidomic analysis revealed that LHE effectively altered lipid composition, especially by lowering triglycerides (TG), diacylglycerols (DG), ceramides (Cer), and hexosyl-1-ceramides (Hex1Cer), with major changes observed in medium- and long-chain TG and phosphatidylethanolamine (PE) levels. Efficacy tests confirmed that LHE reduced sebum production and improved skin texture by shrinking pore size. Conclusions LHE improves sebaceous gland function by reducing lipid overproduction and hyperproliferation through the PPARγ/LXRα/SREBP1 pathway. It also enhances the lipid profile by lowering key lipid molecules like TGs and PEs. Moreover, LHE shows anti-inflammatory and antioxidant effects. These findings suggest its therapeutic potential for sebaceous gland-related conditions and reveal new insights into its mechanism in topical use.
研究领域:
药理学
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民族药理学
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皮肤科学
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分子生物学
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生物化学
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脂质代谢
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植物学
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产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
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2025
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IF 3.3
Xinjing Shi,Qingjing Gao,Wenjing Lu,Yuning Xie,Haolin Zhang,Dong Zhang,Yuning Liu,Qiang Weng
SREBP1 (sterol regulatory element binding protein 1) plays an important role in maintaining lipid balance in mammals. Previous research showed that androgen significantly regulated the secretion of lipid-rich musky odor substances from the scented glands of muskrats. Our investigation provides insights into the pathways through which androgen induces SREBP1 expression and affects seasonal changes in triglyceride synthesis in muskrat scented glands. During the breeding season, pronounced Oil Red O staining was confirmed in the scented glandular tissues, and transmission electron microscopy displayed a marked increase in lipid droplets. The scented glands exhibited a higher triglyceride content, which coincided with augmented circulating testosterone, dihydrotestosterone, as well as increased scented glandular testosterone and dihydrotestosterone concentrations. Transcriptomic, proteomic and metabolomic analyses of the scented glands revealed associations with fatty acid biosynthesis, while plasma metabolomic data indicated an increase in metabolites serving as precursors during the breeding season for de novo fatty acid synthesis. Expression levels of genes and proteins related to lipid synthesis and lipid droplets, as well as FASN activity, were significantly elevated in the breeding season. Immunolocalization studies demonstrated the presence of these proteins in glandular and epithelial cells in both seasons. Moreover, in vitro treatment of the scented glandular cells with testosterone resulted in elevated expressions of triglyceride synthesis-related genes. These findings suggested that androgen modulates triglyceride synthesis to enhance lipid droplet formation via the AR-SREBP1-FASN Axis in the scented glands of muskrats, thereby shedding light on the hormonal regulation of lipid metabolism in seasonal breeders.
研究领域:
分子生物学
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内分泌学
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生物化学
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生殖生物学
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比较生理学
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脂质代谢
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动物生理学
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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）