Biomedicines
·
2024
·Vol. 12
·期 7
·1505
·
IF 3.9
Qi Zhang,Shuang Wu,Qiubing Chen,Yahong Zhang,Cai Zhang,Runting Yin,Zhen Ouyang,Yuan Wei
The prevalence of excessive drinking-related alcoholic liver disease (ALD) is rising, yet therapeutic options remain limited. High alcohol consumption and consequent oxidative metabolism by cytochrome P450 (CYP) can lead to extremely high levels of reactive oxygen species, which overwhelm cellular defenses and harm hepatocytes. Our previous investigations showed that inhibitingCyp2e1using RNA interference reduced the incidence of ALD. However, compensatory mechanisms other than CYP2E1 contribute to oxidative stress in the liver. Therefore, we coupled triple siRNA lipid nanoparticles (LNPs) targetingCyp2e1with two isoenzymesCyp4a10andCyp4a14to treat ALD mouse models fed with Lieber–Decarli ethanol liquid diet for 12 weeks at the early (1st week), middle (5th week), and late (9th week) stages. The administration of triple siRNA LNPs significantly ameliorated chronic alcoholic liver injury in mice, and early treatment achieved the most profound effects. These effects can be attributed to a reduction in oxidative stress and increased expression of antioxidant genes, includingGsh-Px,Gsh-Rd, andSod1. Moreover, we observed the alleviation of inflammation, evidenced by the downregulation ofIl-1β,Il-6,Tnf-α, andTgf-β, and the prevention of excessive lipid synthesis, evidenced by the restoration of the expression ofSrebp1c,Acc, andFas. Finally, triple siRNA treatment maintained normal metabolism in lipid oxidation. In brief, our research examined the possible targets for clinical intervention in ALD by examining the therapeutic effects of triple siRNA LNPs targetingCyp2e1,Cyp4a10, andCyp4a14. The in vivo knockdown of the three genes in this study is suggested as a promising siRNA therapeutic approach for ALD.
研究领域:
肝病学
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分子生物学
·
药理学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2025
·
IF 4.9
Bing Li,Pengjun Zhong,Xueling Zhang,Chengguo Li,Min Luan,Yanlin Chen,Lei Chen,Wu Li,Rihui Wu
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a progressively critical global health concern, with no pharmacological interventions currently approved. Ursodeoxycholic acid (UDCA), an endogenous bile acid utilized in clinical practice, has demonstrated therapeutic potential in treating MASLD. However, the precise mechanisms by which UDCA exerts its hepatoprotective effects in MASLD remain to be fully characterized. We found that UDCA intervention markedly alleviated HFD-induced phenotypes, including hepatic steatosis, inflammation and metabolic disturbances, in high-fat diet (HFD)-fed mice. Mechanistically, UDCA treatment significantly activated hepatic peroxisome proliferator-activated receptor α (PPARα) and Cytochrome P450 family 4 subfamily A member 14 (CYP4A14)-mediated β-fatty acid oxidation. In vitro , treatment with UDCA effectively reduced lipid accumulation and liver enzyme release in AML12 hepatocytes subjected to palmitic acid (PA) and oleic acid (OA) challenge. UDCA administration significantly activated the PPARα-CYP4A14 signaling pathway, however, siRNA-mediated knockdown of these components resulted in a significant reduction of UDCA's protective efficacy in alleviating lipid accumulation in PA/OA-induced cellular models. Additionally, molecular docking and molecular dynamics simulations demonstrated stable interactions between UDCA and CYP4A14, indicating that UDCA may directly regulate CYP4A14 signaling. In conclusion, this study elucidates the CYP4A14-involved PPARα signaling as a novel mechanism by which UDCA exerts its anti-MASLD effects, thereby providing a theoretical foundation for considering UDCA as a potential therapeutic agent for MASLD.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2023
·
IF 14.5
Lijuan Xue,Keanqi Liu,Caixia Yan,Junling Dun,Yexin Xu,Linlin Wu,Huizhu Yang,Huafang Liu,Lin Xie,Guangji Wang,Yan Liang
Nonalcoholic steatohepatitis (NASH) is a spectrum of chronic liver disease characterized by hepatic lipid metabolism disorder. Recent reports emphasized the contribution of triglyceride and diglyceride accumulation to NASH, while the other lipids associated with the NASH pathogenesis remained unexplored. The specific purpose of our study was to explore a novel pathogenesis and treatment strategy of NASH via profiling the metabolic characteristics of lipids. Herein, multi-omics techniques based on LC–Q-TOF/MS, LC–MS/MS and MS imaging were developed and used to screen the action targets related to NASH progress and treatment. A methionine and choline deficient (MCD) diet-induced mouse model of NASH was then constructed, and Schisandra lignans extract (SLE) was applied to alleviate hepatic damage by regulating the lipid metabolism-related enzymes CES2A and CYP4A14. Hepatic lipidomics indicated that MCD-diet led to aberrant accumulation of phosphatidylethanolamines (PEs), and SLE could significantly reduce the accumulation of intrahepatic PEs. Notably, exogenous PE (18:0/18:1) was proved to significantly aggravate the mitochondrial damage and hepatocyte apoptosis. Supplementing PE (18:0/18:1) also deteriorated the NASH progress by up regulating intrahepatic proinflammatory and fibrotic factors, while PE synthase inhibitor exerted a prominent hepatoprotective role. The current work provides new insights into the relationship between PE metabolism and the pathogenesis of NASH.
研究领域:
药理学
·
肝病学
·
脂质组学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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