Journal of Shandong University (Health Sciences) ›› 2020, Vol. 1 ›› Issue (7): 24-31.doi: 10.6040/j.issn.1671-7554.0.2020.0102

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Molecular mechanism of Toll-like receptor 4 in the aggravation of blood lipid accumulation by inhibiting the peroxisome proliferator-activate receptor γ

FU Jieqi, ZHANG Man, ZHANG Xiaolu, LI Hui, CHEN Hong   

  1. Department of MICU, Central Hospital Affiliated To Shenyang Medical College, Shenyang 110024, Liaoning, China
  • Online:2020-07-20 Published:2020-07-10

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Abstract: Objective To investigate the molecular mechanism of Toll-like receptor 4(TLR4)and peroxisome proliferator-activated receptor γ(PPARγ)in the process of lipid accumulation in rat models of high-fat diet and oxidized low-density lipoprotein(oxLDL). Methods A total of 20 healthy male Wistar rats were randomly divided into control group(n=10)and high fat group(n=10). Total cholesterol(TG), triglycerides(TC), high-density lipoprotein(HDL)and low-density lipoprotein(LDL)levels were measured in both groups. The carotid intima-media thickness ratio was detected with HE staining, and the protein expressions of TLR4 and PPARγ were determined with Western blotting. Rat macrophages RAW264.7 were cultured in vitro and stimulated by oxLDL(50 mg/L)to prepare the macrophage models, and TLR4 factors in the macrophages were silenced with siRNA-TLR4 to prepare the TLR4 silencing models. The cells were divided into blank group(group A), oxLDL group(group B), oxLDL+siRNA group(group C), oxLDL+siRNA-TLR4 group(group D), oxLDL+siRNA-TLR4+PPARγ agonist group(group E)and oxLDL +siRNA-TLR4+PPARγ inhibitor group(group F). The lipid accumulation in macrophages was observed with oil red O staining, cholesterol level in macrophages was quantitatively detected, and protein expressions of TLR4 and PPARγ were tested with Western blotting. Results In the animal model experiments, compared with control group, high fat group had significantly increased levels of TG, TC, LDL, ratio of carotid intima-media thickness, and relative expression of TLR4(P<0.01), but decreased levels of serum HDL and PPARγ(P<0.01), and there was a negative correlation between TLR4 and PPARγ (r=-0.928 1, P<0.001). In the oxLDL exposure to macrophages experiments, compared with group A, groups B and C had significantly increased cholesterol content(P<0.01), oil red O particles, optical density(OD)value and relative expression of TLR4, but decreased relative expression of PPARγ (P<0.05). Besides, there was a negative correlation between TLR4 and PPARγ(r=-0.986 7, P<0.001)in group B. Compared with group B, group C had no significant changes in cholesterol content, oil red O particles, OD value and relative expressions of TLR4 and PPARγ(P>0.05). Compared with group B, group D had significantly decreased cholesterol content, oil red O particles, OD value and relative expression of TLR4(P<0.01), but significantly increased relative expression of PPARγ(P<0.05). Compared with group D, group E had significantly decreased cholesterol content, oil red O particles and OD value(P<0.01), but significantly increased relative expression of PPARγ(P<0.05), and the expression of TLR4 remained unchanged(P>0.05). Compared with group D, group F had significantly increased cholesterol content(P<0.01), oil red O particles and OD value, but significantly decreased relative expression of PPARγ(P<0.05), and the relative expression of TLR4 protein did not significantly change(P>0.05). Conclusion The accumulation of blood lipids in cells is involved in the pathogenesis of atherosclerosis(AS). As a protective factor, PPARγ can inhibit the accumulation of blood lipids in macrophages and then participate in AS regulation. As an upstream regulatory site of PPARγ, TLR4 aggravates lipid accumulation by inhibiting the expression of PPARγ, and then interferes with the progression of AS.

Key words: Oxidized low-density lipoprotein, Toll-like receptor 4, Peroxisome proliferator-activated receptor γ, Atherosclerosis, Blood lipids, Cholesterol, Macrophages, Gene silencing

CLC Number: 

  • R543.5
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