Frontiers in Pharmacology
·
2024
·
IF 4.4
Wang Jiahua,Zang Juan,Yu Yang,Liu Yang,Cao Huimin,Guo Ruibo,Zhang Lu,Liu Mo,Zhang Zixu,Li Xuetao,Kong Liang
Background: The preservation of the Lingguizhugan (LGZG) decoction and patient compliance issue often limit the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Hence, herein, an LGZG oral solution was developed for alleviating MASLD. Additionally, the potential mechanisms underlying LGZG-mediated MASLD mitigation were explored.Methods: A MASLD mouse model was constructed using oleic and palmitic acid-induced LO2 cells and a high-fat diet. The apoptosis, lipid deposition, and mouse liver function were analyzed to assess the therapeutic effects of the LGZG oral solution on MASLD. Serum untargeted metabolomics, gut microbiota, bile acid (BA) metabolism, immunohistochemistry, and Western blotting analyses were performed to investigate the potential mechanism of action of LGZG oral solution on MASLD.Results: The LGZG oral solution ameliorated lipid deposition, oxidative stress, inflammation, and pathological damage. Serum untargeted metabolomics results revealed the LGZG-mediated regulation of the primary BA biosynthetic pathway. The 16S ribosomal RNA sequencing of the fecal microbiota showed that LGZG oral solution increased the relative abundance of the BA metabolism-associated Bacteroides, Akkermansia, and decreased that of Lactobacillus. Additionally, the BA metabolism analysis results revealed a decrease in the total taurine-α/β-muricholic acid levels, whereas those of deoxycholic acid were increased, which activated specific receptors in the liver and ileum, including farnesoid X receptor (FXR) and takeda G protein-coupled receptor 5 (TGR5). Activation of FXR resulted in an increase in short heterodimer partner and subsequent inhibition of cholesterol 7α-hydroxylase and sterol regulatory element-binding protein-1c expression, and activation of FXR also results in the upregulation of fibroblast growth factor 15/19 expression, and consequently inhibition of cholesterol 7α-hydroxylase, which correlated with hepatic BA synthesis and lipogenesis, ultimately attenuating lipid deposition and bile acid stasis, thereby improving MASLD.Conclusion: Altogether, the findings of this study suggest that modulating microbiota–BA–FXR/TGR5 signaling pathway may be a potential mechanism of action of LGZG oral solution for the treatment of MASLD.
研究领域:
药理学
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肝病学
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代谢学
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微生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Jiang Huan-guo,Zhan Zhi-kun,Tian Ling-min,Chen Yu-lian,Cai Mei-qun,Ge Guang-bo,Chen Xin,Wei Chuan-liang,Tang Lan
Carboxylesterases CES1 and CES2 are the pivotal hepatic enzymes involved in triglyceride (TG) hydrolysis and prodrug metabolism, yet their expression and activity are suppressed in metabolic dysfunction-associated steatotic liver disease (MASLD). Liver X receptor alpha (LXRα) is known to play a crucial role in maintaining the constitutive expression of CES1 in human liver cells. Oridonin (ORI) is a diterpene derived from a traditional Chinese herb that possesses antitumor, anti-inflammatory, and antimicrobial activities. We previously demonstrated that ORI, as a natural LXRα agonist, activated the LXRα-ATGL/EPT1 pathway, correcting the TG/phosphatidylethanolamine (PE) lipid imbalance induced by obesity and thereby improving MASLD. Here, we investigated the regulatory role of LXRα on CES1/CES2 expression in MASLD liver and elucidated the underlying molecular mechanisms of ORI’s lipid-lowering effects. A high-fat diet (HFD)-induced steatosis model was established in mice. The mice were treated with ORI (100 mg·kg − 1 ·d − 1 , i.g.) from the 16th to the 24th week. RNA-seq analysis in MASLD patients demonstrated that LXRα is a key transcriptional regulator of CES1 and CES2. LXRα knockout (LXRα − / − ) mice exhibited aggravated HFD-induced steatosis and impaired metabolic conversion of the CES1/CES2 substrates, oseltamivir and irinotecan. This deficiency resulted in a corresponding increase in their drug exposure (AUC) by 154.5% and 26.2%, respectively. Mechanistically, LXRα directly bound to liver X receptor response elements (LXREs) in the promoter regions of CES1 (−183/−165 bp) and CES2 (−1870/−1852 bp) to drive transcription in HepG2 cells. Furthermore, ORI (2.5, 5, 10 μM) dose-dependently restored CES1/CES2 expression and activity, reducing lipid accumulation. Silencing of CES1 or CES2 abolished ORI’s lipid-lowering effect, confirming their essential roles. These findings establish the LXRα-CES1/CES2 pathway as a pivotal node integrating hepatic lipid homeostasis and drug metabolism, positioning ORI as a promising therapeutic agent for MASLD.
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产品关联
DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2026
·
IF 5.5
Maoru Li,Zefeng Wang,Huan Zhai,Jiajiao Li,Ji Ma,Bin Qiu
BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is a rapidly growing metabolic disorder with no FDA-approved treatment. Pachymic acid (PA; synonym: 3-O-acetyltumulosic acid), a lanostane-type triterpenoid, shows potential for treating MASLD. However, its mechanisms remain underexplored.ObjectiveThis work evaluated the therapeutic efficacy and mechanisms of PA in treating MASLD.MethodsThe high-cholesterol diet (HCD)-induced zebrafish model, high-fat diet induced C57BL/6 mice model and free fatty acid (FFA)-treated BRL-3A cells was used to assess PA’s anti- MASLD effects in vivo and in vitro.ResultsPA improved lipid metabolism disrupted by HCD, reduced hepatic oxidative stress, as indicated by decreased MDA levels and increased SOD activity, and lowered inflammatory markers, including TNF-α, IL-6, and IL-1β. PA also enhanced antioxidant activity by regulating the Keap1-Nrf2-HO-1 pathway. PA decreased Keap1 mRNA expression induced by reactive oxygen species (ROS), upregulated Nrf2 and HO-1 expression, and promoted Nrf2 nuclear translocation. These effects suggest that PA inhibits ROS production by activating the Keap1-Nrf2-HO-1 pathway and possibly by inhibiting Nrf2 degradation.ConclusionPA improves MASLD through lipid metabolism regulation and antioxidant effects, primarily by activating the Keap1-Nrf2-HO-1 pathway. These findings highlight PA’s potential as a therapeutic agent for MASLD.
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DOI
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
·
2025
·
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
Frontiers in Pharmacology
·
2024
·
IF 4.4
Ting Tai,Yuan-Yuan Shao,Yu-Qi Zheng,Li-Ping Jiang,Hao-Ru Han,Na Yin,Hao-Dong Li,Jin-Zi Ji,Qiong-Yu Mi,Li Yang,Lei Feng,Fu-Yang Duan,Hong-Guang Xie
Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently confers an increased risk of vascular thrombosis; however, the marketed antiplatelet drugs are investigated for the prevention and treatment of MASLD in patients with these coexisting diseases.Methods: To determine whether clopidogrel could ameliorate high-fat diet (HFD)-induced hepatic steatosis in mice and how it works, mice were fed on normal diet or HFD alone or in combination with or without clopidogrel for 14 weeks, and primary mouse hepatocytes were treated with palmitate/oleate alone or in combination with the compounds examined for 24 h. Body weight, liver weight, insulin resistance, triglyceride and total cholesterol content in serum and liver, histological morphology, transcriptomic analysis of mouse liver, and multiple key MASLD-associated genes and proteins were measured, respectively.Results and discussion: Clopidogrel mitigated HFD-induced hepatic steatosis (as measured with oil red O staining and triglyceride kit assay) and reduced elevations in serum aminotransferases, liver weight, and the ratio of liver to body weight. Clopidogrel downregulated the expression of multiple critical lipogenic (Acaca/Acacb, Fasn, Scd1, Elovl6, Mogat1, Pparg, Cd36, and Fabp4), profibrotic (Col1a1, Col1a2, Col3a1, Col4a1, Acta2, and Mmp2), and proinflammatory (Ccl2, Cxcl2, Cxcl10, Il1a, Tlr4, and Nlrp3) genes, and enhanced phosphorylation of AMPK and ACC. However, compound C (an AMPK inhibitor) reversed enhanced phosphorylation of AMPK and ACC in clopidogrel-treated primary mouse hepatocytes and alleviated accumulation of intracellular lipids. We concluded that clopidogrel may prevent and/or reverse HFD-induced hepatic steatosis in mice, suggesting that clopidogrel could be repurposed to fight fatty liver in patients.
研究领域:
药理学
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肝病学
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代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2024
·
IF 27.7
Yilie Liao,Qishan Chen,Lei Liu,Haipeng Huang,Jingyun Sun,Xiaojie Bai,Chenchen Jin,Honghao Li,Fangfang Sun,Xia Xiao,Yahong Zhang,Jia Li,Weiping Han,Suneng Fu
Increased de novo lipogenesis is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity, but the macronutrient carbon source for over half of hepatic fatty acid synthesis remains undetermined. Here, we discover that dietary protein, rather than carbohydrates or fat, is the primary nutritional risk factor for MASLD in humans. Consistently, ex vivo tracing studies identify amino acids as a major carbon supplier for the tricarboxylic acid (TCA) cycle and lipogenesis in isolated mouse hepatocytes. In vivo , dietary amino acids are twice as efficient as glucose in fueling hepatic fatty acid synthesis. The onset of obesity further drives amino acids into fatty acid synthesis through reductive carboxylation, while genetic and chemical interventions that divert amino acid carbon away from lipogenesis alleviate hepatic steatosis. Finally, low-protein diets (LPDs) not only prevent body weight gain in obese mice but also reduce hepatic lipid accumulation and liver damage. Together, this study uncovers the significant role of amino acids in hepatic lipogenesis and suggests a previously unappreciated nutritional intervention target for MASLD.
研究领域:
代谢
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营养
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肝病学
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肥胖研究
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产品关联
DOI
PubMed
高影响因子
METABOLISM-CLINICAL AND EXPERIMENTAL
·
2024
·
IF 10.8
Xu Zhang,Tianxing Chen,Zhenhan Li,Lingfeng Wan,Zhihang Zhou,Ying Xu,Dong Yan,Wei Zhao,Hao Chen
Background & aims Abnormal expression of long noncoding RNAs is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise molecular mechanisms remain unclear. This study explores the roles of noncoding RNA activated by DNA damage (NORAD)/miR-511-3p/Rho-associated protein kinase 2 ( Rock2 ) axis and the NORAD/ROCK2 interaction in the development of MASLD. Methods In vitro and in vivo models of MASLD were created using high-fat diet-fed mice and free fatty acid (FFA)-treated hepatocytes. To examine the relationships between NORAD, miR-511-3p, and ROCK2, we employed bioinformatics, luciferase assays, RNA immunoprecipitation, and biotinylated NORAD pull-down assays. MASLD progression was assessed based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation, white fat growth, and liver fibrosis. Results NORAD and ROCK2 were upregulated, while miR-511-3p was downregulated in MASLD liver tissues and FFA-treated hepatocytes. Mechanistically, NORAD competitively interacted with miR-511-3p to modulate Rock2 mRNA expression, and directly stabilized ROCK2 protein by abrogating its ubiquitination degradation. Functionally, liver-specific knockdown of NORAD or overexpression of miR-511-3p significantly slowed MASLD progression. Overexpression of NORAD or ROCK2 partially reversed miR-511-3p-induced inhibition of MASLD. Additionally, ROCK2 knockdown attenuated NORAD-induced worsening of MASLD. Moreover, overexpressing NORAD or ROCK2 or interfering miR-511-3p influenced resmetirom treatment to suppress MASLD development. Finally, metabolic changes in liver driven by the NORAD/miR-511-3p/ Rock2 axis and NORAD/ROCK2 interaction also influenced white adipose growth, pancreatic β-cell dedifferentiation, and liver fibrosis. Conclusions The NORAD/miR-511-3p/ Rock2 axis and the NORAD/ROCK2 interaction play critical roles in MASLD progression, identifying potential therapeutic targets for its treatment.
研究领域:
分子生物学
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肝脏病学
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代谢研究
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非编码RNA研究
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2024
·Vol. 29
·期 3
·1-13
·
IF 3.4
Yaowei Bai,Kequan Chen,Jiacheng Liu,Yingliang Wang,Chaoyang Wang,Shuguang Ju,Chen Zhou,Wei Yao,Bin Xiong,Chuansheng Zheng
Metabolic dysfunction‑associated steatotic liver disease (MASLD) is an increasingly significant global health burden for which there is currently no effective treatment. The present study aimed to explore the underlying mechanisms and investigate the effects of donafenib and atorvastatin in MASLD. The effects of donafenib and atorvastatin on the activity and lipid metabolism of HepG2 cells were analyzed in vitro. A rat model of MASLD was established induced by a high‑fat diet in vivo. H&E and Oil red O staining were used to observe the improvement in MASLD, western blotting analysis was used to detect the expression of proteins related to fat metabolism and immunofluorescence was used to detect reactive oxygen species (ROS) levels. In vitro, donafenib and atorvastatin inhibited lipid accumulation in HepG2 cells. In vivo, donafenib and atorvastatin activated the AMP‑activated protein kinase (AMPK) pathway, downregulated the expressions of proteins related to fatty acid synthesis (sterol regulatory element‑binding protein‑1, 3‑hydroxy‑3‑methylglutaryl‑CoA reductase and fatty acid synthase) and upregulated the expression of proteins related to fatty acid β‑oxidation (carnitine palmitoyl‑transferase 1C and acyl‑CoA oxidase). The levels of free fatty acids, cholesterol and triglycerides in the liver and serum decreased in all three treatment groups. Additionally, donafenib and atorvastatin reduced oxidative stress in the liver tissue and decreased ROS levels. Low‑dose donafenib combined with atorvastatin improved MASLD by regulating fatty acid metabolism and reducing oxidative stress through activation of the AMPK signaling pathway.
研究领域:
药理学
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肝病学
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代谢学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
·
2025
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IF 3.3
Hong-Yu Li,Wei-Lan Zeng,Yi-Wen Ye,Xin Chen,Ming-Ming Zhang,Yi-Si Chen,Cui-Ting Liu,Zhun-Qiang Zhong,Jing Li,Yan Wang
Glia maturation factor-β (Gmfb), an actin filament debrancher, was initially identified in brain and recently linked to liver diseases. To investigate the role of hepatocyte Gmfb (hep-Gmfb) in liver reparative regeneration, hepatocyte-specific gmfb knockout (HepGKO) and overexpression (HepGOE) zebrafish strains were constructed. Both transgenic and wild-type (WT) zebrafish underwent partial hepatectomy (PHX) or were fed high fat, high cholesterol diets to model metabolism-associated steatotic liver disease (MASLD). Under physiological conditions, the HepGKO, HepGOE, and WT fish displayed similar survival, gross appearance, and liver histology. Following PHX, WT liver gmfb levels positively correlated with cell proliferation and proinflammatory cytokine levels. HepGOE showed enhanced regeneration and reduced liver steatosis compared to WT, while HepGKO exhibited opposite effects. In MASLD, WT liver gmfb increased with disease progression. HepGKO experienced worsening liver enlargement, steatosis, ballooning, inflammation, and endoplasmic reticulum stress, while HepGOE showed improvements. HepGOE liver had the highest cell proliferation, but all three groups showed similar levels of cell apoptosis. Moreover, elevated proinflammatory cytokines were observed across MASLD groups, being the highest in HepGKO and lowest in HepGOE. However, stat3 activation was the lowest in HepGKO and highest in HepGOE, while jnk and mapk/erk activation was consistent across the MASLD groups. In il6-treated primary hepatocytes, gmfb abundance influenced stat3 activation, and hep-gmfb abundance significantly affected actin filaments distribution in hepatocytes both in vivo and vitro. Conclusions: Hep-Gmfb boosts regenerative processes by enhancing hepatocyte proliferation, alleviating fatty liver histological abnormalities, and modulating the Il6/Stat3 signaling, potentially through remodeling of actin-filament network within hepatocytes.
研究领域:
分子生物学
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细胞生物学
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肝脏病学
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发育生物学
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遗传学
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信号转导
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
·
IF 5.6
Hai-Ying Tian,Dao-Jiang Yu,Teng Xie,Meng-Xia Xu,Yu-Hao Wang,Xi-Lu Sun,Xin-Meng Zhou,Ying-Xuan Han,Qing-Qing Liao,Yu-Jie Zhao,Juan Liao,Mohamed El-Kassas,Xiao-Dong Sun,Yuan-Yuan Zhang
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) keeps rising with only a few drugs available. The present study aims to investigate the effects and mechanisms of cordycepin on MASLD. Male C57BL/6 mice were induced with a 90-day high-fat diet (HFD) and intraperitoneal administration with streptozotocin to establish MASLD murine model. Then they were randomly divided into the HFD and cordycepin groups (15, 30, 45 mg/kg). Cordycepin was orally given for 30 days. Serum total cholesterol (TC), triacylglyceride (TG), and aspartate aminotransferase (AST) levels were measured. L02 cells were induced by oleate acid (OA) or lipopolysaccharides (LPS), and treated with cordycepin or combined with inhibitors including chloroquine, 3-Methyladenine, and compound C. Atg7 and Parkin were knocked down in L02 cells using siRNA. Oil Red O and Nile Red staining for measuring lipid deposition. Mitochondria were visualized by transfection with mCherry-TOMM20-N10. Quantitative real-time PCR, Western blotting, and immunofluorescence staining were used to determine expressions of key molecules in inflammation, lipid metabolism, mitochondria homeostasis, and oxidative stress. Cordycepin significantly mitigated lipid deposition and ballooning in the livers of MASLD mice. Serum TC, TG, and AST levels were decreased by cordycepin. Cordycepin alleviated OA-induced lipid deposition and LPS-induced inflammation in L02 cells, attenuated oxidative stress, promoted autophagy, and maintained the autophagic flux by activating AMP-activated protein kinase (AMPK). Cordycepin reduced the accumulation of impaired mitochondria by enhancing Parkin-dependent mitophagy and promoting mitochondrial biogenesis. Cordycepin alleviates MASLD by restoring mitochondrial homeostasis and reducing oxidative stress via activating the Parkin-mediated mitophagy.
研究领域:
药理学
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肝病学
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分子生物学
·
细胞代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Yifu Lyu,Xiuyi Yang,Lei Yang,Jinyu Dai,Huanyu Qin,Yunuo Zhou,Yunan Huang,Yanmei Wang,Di Wu,Qindai Shuai,Qilong Li,Xiaofei Xin,Lifang Yin
Lipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway. We then adopted a three-round screening strategy to optimize the formulation with both high potency and selectivity to deliver siRNA-HIF-1α (siHIF1α) and silibinin (SLB) payloads to hepatocytes. The optimized SLB/siHIF1α-LNPs mediates great siRNA delivery and transfection of hepatocytes. In high fat diet (HFD)- and carbon tetrachloride (CCl 4 )-induced mouse models of MASLD, SLB/siHIF1α-LNPs enabled the silencing of hypoxia inducible factor-1α (HIF-1α), a therapeutic target primarily expressed by hepatocytes, leading to significantly reduced inflammation and liver fibrosis synergized with SLB. Moreover, it is demonstrated the hepatocyte-targeting delivery of SLB/siHIF1α-LNPs has the potential to restore the immune homeostasis by modulating the population of Tregs and cytotoxic T cells in spleen. This proof-of-concept study enable siRNA and small molecule co-delivery to hepatocytes through intrinsic variation of targeting receptors for MASLD therapy.
研究领域:
药学
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分子生物学
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肝病学
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纳米技术
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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）