Neurotensin accelerates atherosclerosis and increases circulating levels of short-chain and saturated triglycerides

Jing Li, Liping Yang, Jun Song, Baoxiang Yan, Andrew Morris, Hunter Moseley, Robert Flight, Chi Wang, Jinze Liu, Heidi L. Weiss, Edward F. Morris, Ilyes Abdelhamid, Mathias J. Gerl, Olle Melander, Susan Smyth, B. Mark Evers

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background and aims: Obesity and type 2 diabetes are significant risk factors for atherosclerotic cardiovascular disease (CVD) worldwide, but the underlying pathophysiological links are poorly understood. Neurotensin (NT), a 13-amino-acid hormone peptide, facilitates intestinal fat absorption and contributes to obesity in mice fed a high-fat diet. Elevated levels of pro-NT (a stable NT precursor produced in equimolar amounts relative to NT) are associated with obesity, type 2 diabetes, and CVD in humans. Whether NT is a causative factor in CVD is unknown. Methods: Nt+/+ and Nt–/– mice were either injected with adeno-associated virus encoding PCSK9 mutants or crossed with Ldlr–/– mice and fed a Western diet. Atherosclerotic plaques were analyzed by en face analysis, Oil Red O and CD68 staining. In humans, we evaluated the association between baseline pro-NT and growth of carotid bulb thickness after 16.4 years. Lipidomic profiles were analyzed. Results: Atherosclerotic plaque formation is attenuated in Nt-deficient mice through mechanisms that are independent of reductions in circulating cholesterol and triglycerides but associated with remodeling of the plasma triglyceride pool. An increasing plasma concentration of pro-NT predicts atherosclerotic events in coronary and cerebral arteries independent of all major traditional risk factors, indicating a strong link between NT and atherosclerosis. This plasma lipid profile analysis confirms the association of pro-NT with remodeling of the plasma triglyceride pool in atherosclerotic events. Conclusions: Our findings are the first to directly link NT to increased atherosclerosis and indicate the potential role for NT in preventive and therapeutic strategies for CVD.

Original languageEnglish
Article number117479
JournalAtherosclerosis
Volume392
DOIs
StatePublished - May 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Keywords

  • Heart disease
  • High-fat diet
  • Neurotensin
  • Obesity
  • Small intestine

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Neurotensin accelerates atherosclerosis and increases circulating levels of short-chain and saturated triglycerides'. Together they form a unique fingerprint.

Cite this