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Minimally modified low-density lipoprotein induces macrophage endoplasmic reticulum stress via toll-like receptor 4

Shutong Yao1, Nana Yang, Guohua Song

  • 1Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China. yst228@126.com

Biochimica Et Biophysica Acta
|April 7, 2012
PubMed

Insights

Minimally modified LDL (mm-LDL) causes cholesterol buildup in macrophages, activating endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) via TLR4. This pathway contributes to atherosclerosis development.

Area of Science:

  • Cellular biology
  • Molecular medicine
  • Cardiovascular research

Background:

  • Minimally modified low-density lipoprotein (mm-LDL) is implicated in atherosclerosis.
  • Endoplasmic reticulum stress (ERS) links cellular processes to atherosclerosis risk factors.
  • The precise mechanisms of mm-LDL-induced lipid accumulation in macrophages involving ERS are not fully understood.

Purpose of the Study:

  • To investigate whether mm-LDL-induced lipid accumulation in macrophages involves ERS.
  • To elucidate the underlying mechanisms of this process, focusing on the role of toll-like receptor 4 (TLR4).

Main Methods:

  • RAW264.7 macrophages were treated with mm-LDL.
  • Lipid droplet accumulation and free cholesterol levels in the endoplasmic reticulum were assessed.
  • Activation of the unfolded protein response (UPR) sensors, activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1), was analyzed.
  • The role of TLR4 and CD36 was evaluated using antibodies and small interfering RNA (siRNA).

Main Results:

  • mm-LDL induced lipid droplet accumulation and increased free cholesterol in the endoplasmic reticulum of macrophages.
  • mm-LDL promoted the nuclear translocation of ATF6 and upregulated p-IRE1 and GRP78 expression.
  • These effects were significantly attenuated by antibodies against TLR4 or CD36, and by TLR4 siRNA.
  • These findings suggest TLR4 mediates mm-LDL-induced ER stress and UPR activation.

Conclusions:

  • mm-LDL induces free cholesterol accumulation in the endoplasmic reticulum of macrophages.
  • This accumulation stimulates endoplasmic reticulum stress and activates the UPR signaling pathway via ATF6 and IRE1.
  • Toll-like receptor 4 (TLR4) plays a key role in mediating these mm-LDL-induced cellular responses, potentially contributing to atherosclerosis.

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