Neurotensin accelerates atherosclerosis and increases circulating levels of short-chain and saturated triglycerides
(2024) In Atherosclerosis- 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... (More)
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.
(Less)
- author
- Li, Jing
; Yang, Liping
; Song, Jun
; Yan, Baoxiang
; Morris, Andrew J.
; Moseley, Hunter
; Flight, Robert
; Wang, Chi
; Liu, Jinpeng
; Weiss, Heidi L.
; Morris, Edward F.
; Abdelhamid, Ilyes
; Gerl, Mathias J.
; Melander, Olle
LU
; Smyth, Susan
and Evers, B. Mark
(Less) - organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- epub
- subject
- keywords
- Heart disease, High-fat diet, Neurotensin, Obesity, Small intestine
- in
- Atherosclerosis
- article number
- 117479
- publisher
- Elsevier
- external identifiers
-
- pmid:38423808
- scopus:85188053490
- ISSN
- 0021-9150
- DOI
- 10.1016/j.atherosclerosis.2024.117479
- language
- English
- LU publication?
- yes
- id
- 03840c25-2224-4131-9bf9-7402e00e14f4
- date added to LUP
- 2024-04-10 11:23:31
- date last changed
- 2024-04-24 14:14:54
@article{03840c25-2224-4131-9bf9-7402e00e14f4,
abstract = {{<p>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<sup>+/+</sup> and Nt<sup>–/–</sup> mice were either injected with adeno-associated virus encoding PCSK9 mutants or crossed with Ldlr<sup>–/–</sup> 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.</p>}},
author = {{Li, Jing and Yang, Liping and Song, Jun and Yan, Baoxiang and Morris, Andrew J. and Moseley, Hunter and Flight, Robert and Wang, Chi and Liu, Jinpeng and Weiss, Heidi L. and Morris, Edward F. and Abdelhamid, Ilyes and Gerl, Mathias J. and Melander, Olle and Smyth, Susan and Evers, B. Mark}},
issn = {{0021-9150}},
keywords = {{Heart disease; High-fat diet; Neurotensin; Obesity; Small intestine}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Atherosclerosis}},
title = {{Neurotensin accelerates atherosclerosis and increases circulating levels of short-chain and saturated triglycerides}},
url = {{http://dx.doi.org/10.1016/j.atherosclerosis.2024.117479}},
doi = {{10.1016/j.atherosclerosis.2024.117479}},
year = {{2024}},
}