Dietary supplementation with long-chain monounsaturated fatty acid isomers decreases atherosclerosis and alters lipoprotein proteomes in LDLr −/− mice

Increasing evidence suggests that neutrophil extracellular traps (NETs) may play a role in promoting atherosclerotic plaque lesions in humans and in murine models. The exact pathways involved in NET-driven atherogenesis remain to be systematically characterized. To assess the extent to which myeloid-specific peptidylarginine deiminase 4 (PAD4) and PAD4-dependent NET formation contribute to atherosclerosis, mice with myeloid-specific deletion of PAD4 were generated and backcrossed to Apoe−/− mice. The kinetics of atherosclerosis development were determined. NETs, but not macrophage extracellular traps, were present in atherosclerotic lesions as early as 3 weeks after initiating high-fat chow. The presence of NETs was associated with the development of atherosclerosis and with inflammatory responses in the aorta. Specific deletion of PAD4 in the myeloid lineage significantly reduced atherosclerosis burden in association with diminished NET formation and reduced inflammatory responses in the aorta. NETs stimulated macrophages to synthesize inflammatory mediators, including IL-1β, CCL2, CXCL1, and CXCL2. Our data support the notion that NETs promote atherosclerosis and that the use of specific PAD4 inhibitors may have therapeutic benefits in this potentially devastating condition.

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“…Atherosclerosis was assessed as previously described ( 20 , 21 ). Briefly, after euthanasia, the vasculature was perfused with PBS.…”

Section: Methodsmentioning

confidence: 99%

Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis

et al. 2018

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“…A few studies have, however, used diets supplemented with concentrated LC-MUFA to investigate the effects attributed specifically to this class of fatty acids. This type of experimental design has investigated the health effects of LC-MUFA on atherogenesis, obesity-induced inflammation, glucose and lipid metabolism, and the expression of associated genes in different animal models (Halvorsen et al, 2001;Yang et al, 2011d;Yang et al, 2013;Yang et al, 2015;Yang et al, 2016a;Yang et al, 2017). From these studies, it can be concluded that LC-MUFA decrease atherosclerotic lesion formation, reduce cholesterol efflux and alter gene expression related to inflammation, lipid metabolism and energy expenditure in different tissues ( Figure 5).…”

Section: Monounsaturated Fatty Acidsmentioning

confidence: 99%

“… Reported effects of concentrated LC-MUFA on gene expression related to fatty acid oxidation, energy consumption, lipogenesis, and inflammation in the liver and adipose tissue, as well as plasma levels of various compounds. C1qR1, complement component 1q receptor; CD36, fatty acid translocase; CPT1a, carnitine palmitoyltransferase 1a; CRP, C-reactive protein; CS, citrate synthase; CyP7a1, cholesterol 7 alpha-hydroxylase (cytochrome P450 7A1); EFGR, epidermal growth factor receptor; FA, free fatty acids; LDL-C, low-density lipoprotein cholesterol; LPL, lipoprotein lipase; MAC-1, macrophage-1 antigen; M-CSF, macrophage colony-stimulating factor; MMP-3, matrix metalloproteinase-3; PPAR, peroxisome proliferator-activated receptor; SAA3, serum amyloid A3; SCD-1, stearoyl-CoA desaturase-1; TC, total cholesterol; UCP, uncoupling protein (summarized from Yang et al., 2011d ; Yang et al., 2013 ; Yang et al., 2015 ; Yang et al., 2016a ; Yang et al., 2017 ). …”

Section: The Main Components Of the Oil From Cf Anmentioning

confidence: 99%

“…This was associated with reduced adipocyte size. LC-MUFA have also been reported to decrease atherosclerosis via PPAR signaling ( Yang et al., 2016a ; Yang et al., 2017 ). Pparα, pparγ, and their target genes Cyp7a1 (encoding cholesterol 7α-hydroxylase or bile acid synthase) and Adipor2 (gene for adiponectin 2 receptor) were reported to be upregulated in the liver of the LC-MUFA fed mice ( Yang et al., 2016a ).…”

Section: The Main Components Of the Oil From Cf Anmentioning

confidence: 99%

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Possible Health Effects of a Wax Ester Rich Marine Oil

et al. 2020

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The consumption of seafood and the use of fish oil for the production of nutraceuticals and fish feed have increased over the past decades due the high content of long-chain polyunsaturated omega-3 fatty acids. This increase has put pressure on the sustainability of fisheries. One way to overcome the limited supply of fish oil is to harvest lower in the marine food web. Calanus finmarchicus, feeding on phytoplankton, is a small copepod constituting a considerable biomass in the North Atlantic and is a novel source of omega-3 fatty acids. The oil is, however, different from other commercial marine oils in terms of chemistry and, possibly, bioactivity since it contains wax esters. Wax esters are fatty acids that are esterified with alcohols. In addition to the long-chain polyunsaturated omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the oil is also rich in stearidonic acid (SDA), long-chain monounsaturated fatty acids, and the long-chain fatty alcohols eicosenol and docosenol. Recent animal studies have indicated antiinflammatory and anti-obesogenic actions of this copepod oil beyond that provided by EPA and DHA. This review will discuss potential mechanisms behind these beneficial effects of the oil, focusing on the impact of the various components of the oil. The health effects of EPA and DHA are well recognized, whereas long-chain monounsaturated fatty acids and long-chain fatty alcohols have to a large degree been overlooked in relation to human health. Recently, however the fatty alcohols have received interest as potential targets for improved health via conversion to their corresponding fatty acids. Together, the different lipid components of the oil from C. finmarchicus may have potential as nutraceuticals for reducing obesity and obesity-related metabolic disorders.

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“…Obesity and insulin resistance are commonly associated with hyperlipidemia and high caloric fat- enriched diets are widely accepted to induce hyperlipidemia [ 26 ]. A western-type diet (TD.88137) was chosen for these studies for its ability to induce hypercholesterolemia, obesity and atherosclerosis depending on the genetic background of the mice used for study [ 24 , 27 , 28 ]. Previous studies have shown that 16 weeks of WD regime is sufficient to induce severe hypercholesterolemia in mice [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Mice lacking global Stap1 expression do not manifest hypercholesterolemia

et al. 2020

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Background Autosomal dominant familial hypercholesterolemia (ADH; MIM#143890) is one of the most common monogenic disorders characterized by elevated circulatory LDL cholesterol. Initial studies in humans with ADH identified a potential relationship with variants of the gene encoding signal transducing adaptor family member protein 1 (STAP1; MIM#604298). However, subsequent studies have been contradictory. In this study, mice lacking global Stap1 expression (Stap1−/−) were characterized under standard chow and a 42% kcal western diet (WD). Methods Mice were studied for changes in different metabolic parameters before and after a 16-week WD regime. Growth curves, body fats, circulatory lipids, parameters of glucose homeostasis, and liver architecture were studied for comparisons. Results Surprisingly, Stap1−/− mice fed the 16-week WD demonstrated no marked differences in any of the metabolic parameters compared to Stap1+/+ mice. Furthermore, hepatic architecture and cholesterol content in FPLC-isolated lipoprotein fractions also remained comparable to wild-type mice. Conclusion These results strongly suggest that STAP1 does not alter lipid levels, that a western diet did not exacerbate a lipid disorder in Stap1 deficient mice and support the contention that it is not causative for hyperlipidemia in ADH patients. These results support other published studies also questioning the role of this locus in human hypercholesterolemia.

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Dietary supplementation with long-chain monounsaturated fatty acid isomers decreases atherosclerosis and alters lipoprotein proteomes in LDLr −/− mice

Abstract: Dietary supplementation with the LCMUFA isomers C20:1 or C22:1 was equally effective in reducing atherosclerosis in LDLrmice and this may partly occur through activation of the Ppar signaling pathways and favorable alterations in the proteome of lipoproteins.

Cited by 19 publications

References 21 publications

Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis

Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis

Possible Health Effects of a Wax Ester Rich Marine Oil

Mice lacking global Stap1 expression do not manifest hypercholesterolemia

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