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Volume 42 Issue 9
Sep.  2026
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Article Navigation >  Journal of Clinical Hepatology  > 2026  >  42(9): 2093-2105

Effect of macrophage lipolysis-stimulated lipoprotein receptor deficiency on a mouse model of metabolic dysfunction-associated steatohepatitis

DOI: 10.12449/JCH260914
  • 1.

    Department of Physiology，School of Basic Medical Sciences，Shandong Medical and Pharmaceutical University，Yantai，Shandong 264003，China

  • 2.

    Shandong Engineering Research Center of Molecular Medicine for Renal Diseases，Yantai，Shandong 264003，China

  • 3.

    Department of Medical Genetics and Cell Biology，School of Basic Medical Sciences，Shandong Medical and Pharmaceutical University，Yantai，Shandong 264003，China

Research funding:

General Program of the National Natural Science Foundation of China (32371172)

More Information
  • Corresponding author: Gong Yongfeng， ygong@bzmc.edu.cn （ORCID： 0000-0001-5151-2346）; Ma Cai， macai@bzmc.edu.cn （ORCID： 0000-0003-4101-2262）
  • Received Date: 2025-12-26
  • Accepted Date: 2026-05-08
  • Published Date: 2026-09-25
    Abstract
  •   Objective  To investigate whether macrophage lipolysis-stimulated lipoprotein receptor （LSR） deficiency affects the progression of metabolic dysfunction-associated steatohepatitis （MASH） by activating the Yes-associated protein （YAP） signaling pathway.  Methods  Male wild-type （WT） mice and macrophage-specific Lsr knockout （LsrMφKO， KO） mice， with an age of 8 weeks and similar body weights， were selected and fed with a normal diet， a high-fat diet （HFD）， or a high-fat high-cholesterol （HFHC） diet for 30 weeks. HE staining and oil red O staining were used to evaluate liver pathological changes； immunofluorescent staining was used to measure the expression levels of F4/80 and α-smooth muscle actin； RT-qPCR and Western blot were used to measure the levels of markers associated with lipid metabolism， inflammation， and fibrosis. Bone marrow transplantation rescue experiments （WT→KO vs KO→KO groups） were conducted to explore the functional role of LSR in macrophages. At the cellular level， hepatic macrophages were isolated from WT and KO mice to measure the expression levels of YAP signaling pathway-related proteins and their downstream target genes， and in addition， these cells were treated in vitro with verteporfin （VP）， a specific inhibitor of YAP， to verify the regulatory effect of this pathway on the expression of inflammatory factors. The independent samples t-test was used for comparison of normally distributed measurement data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed measurement data.  Results  Under the condition of normal diet， there were no significant differences in hepatic indicators between WT and KO mice. KOmice fed an HFD or HFHC diet showed a significant increase in hepatic lipid droplet accumulation， accompanied by lipid metabolism disorder and significant increases in the levels of indicators associated with inflammation and fibrosis （P<0.05）. Bone marrow transplantation experiments confirmed that compared with the KO→KO group， the WT→KO group had significant alleviation of liver injury （P<0.05）. Mechanistic studies showed that there were significant reductions in the levels of phosphorylated large tumor suppressor kinase 1 （LATS1） and phosphorylated YAP and significant increases in the expression levels of total YAP protein and its downstream target genes in hepatic macrophages of KO mice （P<0.05）. In vitro VP intervention significantly inhibited the expression levels of inflammatory factors in hepatic macrophages isolated from KO mice （P<0.05）.  Conclusion  Macrophage LSR deficiency activates the YAP signaling pathway by inhibiting LATS1/2 kinase activity and promotes the expression of inflammatory factors， thereby accelerating the progression of liver injury in a mouse model of MASH.

     

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