LSS deficiency ameliorates MASLD by downregulating NPC1L1 and activating the CD36/TLR4/JNK pathway
10.19405/j.cnki.issn1000–1492.2026.05 003
- VernacularTitle:LSS缺失通过下调NPC1L1与激活CD36/TLR4/JNK通路改善MASLD
- Author:
Zihan WANG
1
;
Hongmei BAI
1
;
Qingya HE
1
;
Wenjing ZHOU
1
;
Jian ZHONG
1
;
Xiaoli JIANG
1
;
Sumei ZHANG
1
;
Shengquan ZHANG
1
Author Information
1. Department of Biochemistry and Molecular Biology， School of Basic Medical Sciences， Anhui Medical University， Hefei 230032
- Publication Type:Journal Article
- Keywords:
metabolic dysfunction-associated steatotic liver disease;
lanosterol synthase;
gut-liver axis;
cholesterol absorption;
gut immunity;
fatty liver model
- From:
Acta Universitatis Medicinalis Anhui
2026;61(5):812-818
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo 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. MethodsLSS 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 assessed 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 employed to examine the mRNA expression of TLR4 and IL-6. ResultsLSS+/- mice were successfully validated by genotyping 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 vacuoles. In contrast， compared with HFD-fed WT mice， HFD-fed LSS+/- mice displayed significantly attenuated hepatic lipid deposition and reduced serum ALT levels （P<0.05）. Immunohistochemical analysis revealed that， compared 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 significantly 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， compared 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. ConclusionLSS deficiency counteracts hepatic lipid deposition by orchestrating a synergistic reprogramming involving restricted intestinal cholesterol absorption， enhanced fatty acid utilization， and activation of immune pathways， suggesting intestinal LSS as a potential therapeutic target of MASLD.
