Highlights
- •Inducible phospholipid transfer protein (PLTP) deficiency reduces plasma cholesterol levels and very low-density lipoproteins (VLDL) production.
- •Inducible PLTP deficiency attenuates AAV8-PCSK9- and Western-type diet-induced atherosclerosis progression.
- •Poor regression of atherosclerotic plaques after low-density lipoprotein cholesterol lowering in mice can be overcome by PLTP depletion.
- •Inhibiting PLTP in patients with atherosclerosis could be an effective approach for the treatment of the disease.
Abstract
Background and aims
Atherosclerosis progression and regression studies are related to its prevention and
treatment. Although we have gained extensive knowledge on germline phospholipid transfer
protein (PLTP) deficiency, the effect of inducible PLTP deficiency in atherosclerosis
remains unexplored.
Methods
We generated inducible PLTP (iPLTP)-knockout (KO) mice and measured their plasma lipid
levels after feeding a normal chow or a Western-type diet. Adenovirus associated virus-proprotein
convertase subtilisin/kexin type 9 (AAV-PCSK9) was used to induce hypercholesterolemia
in the mice. Collars were placed around the common carotid arteries, and atherosclerosis
progression and regression in the carotid arteries and aortic roots were evaluated.
Results
On a normal chow diet, iPLTP-KO mice exhibited decreased cholesterol, phospholipid,
apoA-I, and apoB levels compared with control mice. Furthermore, the overall amount
of high-density lipoprotein (HDL) particles was reduced in these mice, but this effect
was more profound for larger HDL particles. On a Western-type diet, iPLTP-KO mice
again exhibited reduced levels of all tested lipids, even though the basal lipid levels
were increased. Additionally, these mice displayed significantly reduced atherosclerotic
plaque sizes with increased plaque stability. Importantly, inducible PLTP deficiency
significantly ameliorated atherosclerosis by reducing the size of established plaques
and the number of macrophages in the plaques without causing lipid accumulation in
the liver.
Conclusions
Induced PLTP deficiency in adult mice reduces plasma total cholesterol and triglycerides,
prevents atherosclerosis progression, and promotes atherosclerosis regression. Thus,
PLTP inhibition is a promising therapeutic approach for atherosclerosis.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Plasma phospholipid transfer protein enhances transfer and exchange of phospholipids between very low density lipoproteins and high density lipoproteins during lipolysis.J. Lipid Res. 1985; 26: 842-851
- Human plasma phospholipid transfer protein causes high density lipoprotein conversion.J. Biol. Chem. 1993; 268: 4032-4036
- Nature. 2010; 466: 707-713
- High plasma phospholipid transfer protein levels as a risk factor for coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1857-1862
- Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility.Circulation. 2010; 122: 470-477
- Plasma lipid transfer proteins and cardiovascular disease. The Framingham Heart Study.Atherosclerosis. 2013; 228: 230-236
- Relation of baseline plasma phospholipid transfer protein (PLTP) activity to left ventricular systolic dysfunction in patients referred for coronary angiography.Atherosclerosis. 2009; 207: 261-265
- Elevated baseline plasma phospholipid protein (PLTP) levels are an independent predictor of long-term all-cause mortality in patients with diabetes mellitus and known or suspected coronary artery disease.Atherosclerosis. 2015; 239: 503-508
- Apolipoprotein B secretion and atherosclerosis are decreased in mice with phospholipid-transfer protein deficiency.Nat. Med. 2001; 7: 847-852
- Increased risk of atherosclerosis by elevated plasma levels of phospholipid transfer protein.J. Biol. Chem. 2002; 277: 48938-48943
- Liver-specific deficiency of serine palmitoyltransferase subunit 2 decreases plasma sphingomyelin and increases apolipoprotein E levels.J. Biol. Chem. 2009; 284: 27010-27019
- Liver serine palmitoyltransferase activity deficiency in early life impairs adherens junctions and promotes tumorigenesis.Hepatology. 2016; 64: 2089-2102
- The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.Science. 2005; 310: 1642-1646
- LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice.Biochem. J. 2011; 434: 49-60
- Liver-specific phospholipid transfer protein deficiency reduces high-density lipoprotein and non-high-density lipoprotein production.Arterioscler. Thromb. Vasc. Biol. 2013; 9: 2058-2064
- A wild-type mouse-based model for the regression of inflammation in atherosclerosis.PloS One. 2017; 12e0173975
- Quantitative lipoprotein subclass and low molecular weight metabolite analysis in human serum and plasma by (1)H NMR spectroscopy in a multilaboratory trial.Anal. Chem. 2018; 90: 11962-11971
- Eliminating the dication-induced intersample chemical-shift variations for NMR-based biofluid metabonomic analysis.Analyst. 2012; 137: 4209-4219
- Evacetrapib reduces prebeta-1 HDL in patients with atherosclerotic cardiovascular disease or diabetes.Atherosclerosis. 2019; 285: 147-152
- Adipocyte phospholipid transfer protein and lipoprotein metabolism.Arterioscler. Thromb. Vasc. Biol. 2015; 35: 316-322
- Fibromuscular cap composition is important for the stability of established atherosclerotic plaques in mature WHHL rabbits treated with statins.Atherosclerosis. 2001; 157: 75-84
- Macrophage lysophosphatidylcholine acyltransferase 3 deficiency-mediated inflammation is not sufficient to induce atherosclerosis in a mouse model.Front Cardiovasc Med. 2018; 5: 192
- Novel reversible model of atherosclerosis and regression using oligonucleotide regulation of the LDL receptor.Circ. Res. 2018; 122: 560-567
- Selective reduction in the sphingomyelin content of atherogenic lipoproteins inhibits their retention in murine aortas and the subsequent development of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2114-2120
- Molecular regulation of HDL metabolism and function: implications for novel therapies.J. Clin. Invest. 2006; 116: 3090-3100
- Phospholipid transfer protein destabilizes mouse atherosclerotic plaque.Arterioscler. Thromb. Vasc. Biol. 2014; 34: 2537-2544
- Phospholipid transfer protein deficiency protects circulating lipoproteins from oxidation due to the enhanced accumulation of vitamin E.J. Biol. Chem. 2002; 277: 31850-31856
- Dramatic remodeling of advanced atherosclerotic plaques of the apolipoprotein E-deficient mouse in a novel transplantation model.J. Vasc. Surg. 2001; 34: 541-547
- Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques.Circulation. 2011; 123: 989-998
- Effects of native and myeloperoxidase-modified apolipoprotein a-I on reverse cholesterol transport and atherosclerosis in mice.Arterioscler. Thromb. Vasc. Biol. 2014; 34: 779-789
- Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.J. Clin. Invest. 1999; 103: 907-914
- Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122
- Plasma phospholipid transfer protein. Adenovirus-mediated overexpression in mice leads to decreased plasma high density lipoprotein (HDL) and enhanced hepatic uptake of phospholipids and cholesteryl esters from HDL.J. Biol. Chem. 1997; 272: 27393-27400
- Regression of atherosclerosis: the journey from the liver to the plaque and back.Arterioscler. Thromb. Vasc. Biol. 2016; 36: 226-235
- Overexpression and deletion of phospholipid transfer protein reduce HDL mass and cholesterol efflux capacity but not macrophage reverse cholesterol transport.J. Lipid Res. 2017; 58: 731-741
- Prodomain of furin promotes phospholipid transfer protein proteasomal degradation in hepatocytes.J Am Heart Assoc. 2018; 7
- LXR-SREBP-1c-phospholipid transfer protein axis controls very low density lipoprotein (VLDL) particle size.J. Biol. Chem. 2010; 285: 6801-6810
- The role of the LDL receptor in apolipoprotein B secretion.J. Clin. Invest. 2000; 105: 521-532
- Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 13045-13050
Article Info
Publication History
Published online: March 12, 2021
Accepted:
March 11,
2021
Received in revised form:
February 23,
2021
Received:
November 27,
2020
Identification
Copyright
© 2021 Elsevier B.V. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- PLTP deficiency-mediated atherosclerosis regression could be related to sphinogosine-1-phosphate reductionAtherosclerosis
- PreviewWe appreciate the positive comment, from Drs. Menno Hoekstra, Ezra J. van der Wel, and Miranda Van Eck, on our recent work of PLTP deficiency-mediated atherosclerosis regression [1]. We agree that the lesion regression effect observed by us can also be attributed to the effect of PLTP deficiency specifically in macrophages, although the mechanism remains unclear.
- Full-Text
- Preview
