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  3. C-reactive protein exacerbates high-fat diet-induced atherosclerosis via a liver-to-vessel axis that determines therapeutic efficacy of atorvastatin

C-reactive protein exacerbates high-fat diet-induced atherosclerosis via a liver-to-vessel axis that determines therapeutic efficacy of atorvastatin

  • Atherosclerosis. 2026 Jan:412:120594. doi: 10.1016/j.atherosclerosis.2025.120594.
Yu Fu 1,  Yu-Xin Hua 1,  Ya-Li Zhang 2,  Chen-Yang Zhang 2,  Hai-Yun Li 2,  Ivan Melnikov 3,  Zufar A Gabbasov 3,  Yi Wu 4,  En-Qi Liu 5,  Shang-Rong Ji 6
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, PR China.
  • 2 MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
  • 3 National Medical Research Center of Cardiology, 15A Akademika Chazova street, 121552, Moscow, Russia.
  • 4 MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. Electronic address: [email protected].
  • 5 MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. Electronic address: [email protected].
  • 6 MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, PR China. Electronic address: [email protected].
PMID: 41319376 DOI: 10.1016/j.atherosclerosis.2025.120594
Abstract

Background and aims: C-reactive protein (CRP) is a liver-derived soluble marker of inflammation whose levels can predict the risk of atherosclerotic Cardiovascular Disease and therapeutic efficacy of statins. Intriguingly, however, CRP is not considered as a mediator of atherosclerosis based primarily on studies examining chow diet (CD)-fed mice. The aim of this study is to investigate the role of CRP in high-fat diet (HFD)-induced atherosclerosis, which models a more prevalent scenario in the real world, and to clarify its impact on Atorvastatin treatment.

Methods: Apoe-sufficient or -deficient mice with or without Crp knockout were fed with CD, HFD, or methionine- and choline-deficient diet, or subjected to carotid artery ligation or Atorvastatin treatment. Hepatic, vascular, and metabolic indexes were then analyzed. The effects of CRP on lipid droplet formation were examined by cellular assays.

Results: Knockout of Crp in Apoe-deficient mice does not affect the progression of atherosclerosis under CD feeding, but significantly reduces plaque burden under HFD feeding. The pro-atherosclerotic effects of Crp are not due to direct modulation of vascular inflammation, but appear to be the result of enhanced lipid accumulation in the liver and the ensuing aggravation of hyperlipidemia. Mechanistically, Crp enhances hepatic lipid accumulation by upregulating Cidea to promote the formation of enlarged lipid droplets in hepatocytes. We further show that the therapeutic efficacy of Atorvastatin on HFD-induced atherosclerosis in Apoe-deficient mice is largely dependent on Crp.

Conclusions: Our findings identify a previously unrecognized role of CRP in enhancing hepatic lipid accumulation under stresses induced by dietary or genetic factors, which underlies its secondary impact on atherosclerosis and determines the therapeutic efficacy of Atorvastatin.

Keywords

Atherosclerosis; C-reactive protein; Inflammation; Lipid droplet; Liver.

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