安徽医科大学学报2026，Vol.61Issue(5)：812-818,7.DOI:10.19405/j.cnki.issn1000-1492.2026.05.003
LSS缺失通过下调NPC1L1与激活CD36/TLR4/JNK通路改善MASLD
LSS deficiency ameliorates MASLD by downregulating NPC1L1 and activating the CD36/TLR4/JNK pathway
摘要
Abstract
Objective To investigate whether intestinal deficiency of lanosterol synthase(LSS),a key enzyme in cholesterol synthesis,influences the progression of metabolic dysfunction-associated steatotic liver disease(MASLD)by regulating intestinal cholesterol absorption and immune response.Methods LSS heterozygous knockout(LSS+/-)mice and wild-type(WT)controls were generated using CRISPR/Cas9 technology and fed either a high-fat diet(HFD)or regular chow(CHOW).The model was validated by genotyping.Hepatic steatosis was as-sessed by HE and oil red O staining.Immunohistochemistry was used to detect the localization and expression of NPC1L1 and CD36 proteins in the intestine.Western blot analysis was performed to measure JNK phosphorylation and TLR4 protein levels in intestinal tissues.Real-time quantitative polymerase chain reaction(qPCR)was em-ployed to examine the mRNA expression of TLR4 and IL-6.Results LSS+/-mice were successfully validated by ge-notyping and reduced intestinal LSS protein expression.HE and oil red O staining of liver sections showed that,compared with WT mice fed a CHOW diet,WT mice fed a HFD exhibited a marked increase in hepatic lipid vacu-oles.In contrast,compared with HFD-fed WT mice,HFD-fed LSS+/-mice displayed significantly attenuated he-patic lipid deposition and reduced serum ALT levels(P<0.05).Immunohistochemical analysis revealed that,com-pared with WT mice,the expression of the cholesterol absorption protein NPC1L1 in the intestinal villi of LSS+/-mice was downregulated under both CHOW and HFD conditions(PHFD<0.001).Conversely,the expression of the fatty acid transporter CD36 was upregulated in the intestines of LSS+/-mice(PCHOW<0.05,PHFD<0.01).Western blot analysis demonstrated that,compared with WT mice,TLR4 protein expression in the intestines of LSS+/-mice significantly increased under both CHOW and HFD conditions(both P<0.05).JNK phosphorylation level was sig-nificantly elevated in LSS+/-mice under CHOW condition(both P<0.05).Under HFD condition,total JNK protein expression increased,but its phosphorylation level showed no significant change.qPCR analysis showed that,com-pared with WT mice,the mRNA levels of TLR4(PCHOW<0.01,PHFD<0.000 1)and IL-6(PCHOW<0.001,PHFD<0.01)were significantly upregulated in the intestines of LSS+/-mice.Conclusion LSS deficiency counteracts he-patic lipid deposition by orchestrating a synergistic reprogramming involving restricted intestinal cholesterol absorp-tion,enhanced fatty acid utilization,and activation of immune pathways,suggesting intestinal LSS as a potential therapeutic target of MASLD.关键词
代谢障碍相关脂肪肝病/LSS/肠-肝轴/胆固醇吸收/肠道免疫/脂肪肝模型Key words
metabolic dysfunction-associated steatotic liver disease/lanosterol synthase/gut-liver axis/cholesterol absorption/gut immunity/fatty liver model分类
医药卫生引用本文复制引用
王子涵,白红枚,何清雅,周文静,钟健,江小丽,张素梅,张胜权..LSS缺失通过下调NPC1L1与激活CD36/TLR4/JNK通路改善MASLD[J].安徽医科大学学报,2026,61(5):812-818,7.基金项目
安徽省自然科学基金项目(编号:2108085MH266) Natural Science Foundation of Anhui Province(No.2108085MH266) （编号:2108085MH266）
