Botanical oils enriched in n-6 and n-3 FADS2 products are equally effective in preventing atherosclerosis and fatty liver

Shewale, Swapnil V.; Boudyguina, Elena; Zhu, Xuewei; Shen, Lanxiao; Hutchins, Patrick M.; Barkley, Robert M.; Murphy, Robert C.; Parks, John S.

doi:10.1194/jlr.m059170

Cited by 20 publications

(34 citation statements)

References 71 publications

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“…FADS2 in the BO (11.4% 18:3 n-6) and EO (6% 18:4 n-3) ADs. AD FA compositions are given in Table 1 and are similar to those published previously (31), except that -linolenic acid content (2.3% energy) was approximately half that of the previous study (3.9% energy) because a different source of BO was used. AD feeding over 16 weeks resulted in uniform food consumption (3-4 g/day/ mouse), body weight gain, and terminal liver, spleen, and gonadal adipose/body weight ratios among all groups irrespective of leukocyte GPR120/FFAR4 expression (data not shown).…”

Section: Plasma Lipid and Lipoprotein Analysissupporting

confidence: 71%

“…Liver sections of WT and KO mice fed the same AD had similar morphological appearance by hematoxylin and eosin and CD68 immunohistochemistry staining (data not shown). Thus, reduced hepatosteatosis in FO-, EO-, and BO-fed mice versus PO-fed mice was independent of leukocyte GPR120/FFAR4 expression and likely occurs via reduced SREBP1 activation and lipogenic gene expression (31). Previous reports have shown a macrophage phenotype switch from M2 to M1 in GPR120/FFAR4 KO versus WT mice fed a high-fat diet containing n-3 PUFA or a selective GPR120/FFAR4 agonist (7,9).…”

Section: Leukocyte Gpr120/ffar4 Does Not Affect Hepatosteatosismentioning

confidence: 95%

“…4B). However, FO-, EO-, and BO-fed GPR120/FFAR4 KO mice had increased M1 (MCP-1, TNF-, IL-6, and IL-1) gene expression macrophage chemotaxis ex vivo and result in reduced aortic root CD68+ intimal area in LDLrKO mice (31). We hypothesized that activated leukocyte GPR120/FFAR4 may limit monocyte trafficking into aortic root intima and performed monocyte-labeling experiments to test our hypothesis.…”

Section: Leukocyte Gpr120/ffar4 Does Not Affect Hepatosteatosismentioning

confidence: 99%

“…1). We previously demonstrated that percentage FA enrichment in plasma and liver phospholipids was similar to that in RBCs (31).…”

Section: Plasma Lipid and Lipoprotein Analysismentioning

confidence: 99%

“…ADs were prepared by the diet kitchen in the Department of Pathology at Wake Forest School of Medicine as previously described (32). Detailed composition and quality control data for similar ADs have been published (31,33).…”

Section: Animals and Atherogenic Dietsmentioning

confidence: 99%

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In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice

Shewale

Brown

et al. 2017

Journal of Lipid Research

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and GPR120/FFAR4 that are activated by short-, medium-, or long-chain FAs (1-6). GPR120/FFAR4 is highly expressed in intestine, adrenals, lung, adipose tissue, and macrophages, and is described as the n-3 PUFA receptor (7). Upon activation by n-3 PUFA, GPR120/FFAR4 inhibits transforming growth factor -activated kinase 1 activation, resulting in attenuation of IKKB/NF-B and JNK/AP1 signaling (7). GPR120/FFAR4 expression regulates obesity in mice and humans; a nonsynonymous mutation (p.R270H) inhibited GPR120/FFAR4 signaling activity, resulting in increased risk of obesity in European populations (8). In vivo, selective activation of GPR120/FFAR4 by n-3 PUFAs is anti-inflammatory and insulin sensitizing (7,8). High-fat diet-fed GPR120/FFAR4 KO mice versus WT counterparts supplemented with n-3 PUFA or a selective GPR120/ FFAR4 agonist (cpdA) (9) have: 1) increased adipose tissue F4/80+ macrophage infiltration and pro-inflammatory/ M1 gene expression, 2) increased M1 gene expression in lipopolysaccharide-stimulated peritoneal macrophages, and 3) increased insulin resistance. Collectively, these findings highlight the anti-inflammatory potential of macrophage GPR120/FFAR4 activation by n-3 PUFA. However, the impact of GPR120/FFAR4 expression on atherosclerosis progression, particularly in the context of dietary FA composition, is unknown.Abstract G protein-coupled receptor (GPR)120/FFA receptor (FFAR)4 (GPR120/FFAR4) activation by n-3 PUFAs attenuates inflammation, but its impact on atherosclerosis is unknown. We determined whether in vivo activation of leukocyte GPR120/FFAR4 by n-3 versus n-6 PUFAs is atheroprotective. Leukocyte GPR120/FFAR4 WT or KO mice in the LDL receptor KO background were generated by bone marrow transplantation. Mice were fed one of the four atherogenic diets containing 0.2% cholesterol and 10% calories as palm oil (PO) + 10% calories as: 1) PO, 2) fish oil (FO; 20:5 n-3 and 22:6 n-3 enriched), 3) echium oil (EO; 18:4 n-3 enriched), or 4) borage oil (BO; 18:3 n-6 enriched) for 16 weeks. Compared with PO, mice fed BO, EO, and FO had significantly reduced plasma cholesterol, TG, VLDL cholesterol, hepatic neutral lipid, and atherosclerosis that were equivalent for WT and KO mice. In BO-, EO-, and FO-fed mice, but not PO-fed mice, lack of leukocyte GPR120/ FFAR4 resulted in neutrophilia, pro-inflammatory Ly6C hi monocytosis, increased aortic root monocyte recruitment, and increased hepatic inflammatory gene expression. In conclusion, leukocyte GPR120 expression has minimal effects on dietary PUFA-induced plasma lipid/lipoprotein reduction and atheroprotection, and there is no distinction between n-3 versus n-6 PUFAs in activating anti-inflammatory effects of leukocyte GPR120/FFAR4 in vivo.

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Section: Plasma Lipid and Lipoprotein Analysissupporting

confidence: 71%

Section: Leukocyte Gpr120/ffar4 Does Not Affect Hepatosteatosismentioning

confidence: 95%

Section: Leukocyte Gpr120/ffar4 Does Not Affect Hepatosteatosismentioning

confidence: 99%

“…1). We previously demonstrated that percentage FA enrichment in plasma and liver phospholipids was similar to that in RBCs (31).…”

Section: Plasma Lipid and Lipoprotein Analysismentioning

confidence: 99%

Section: Animals and Atherogenic Dietsmentioning

confidence: 99%

See 3 more Smart Citations

In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice

Shewale

Brown

et al. 2017

Journal of Lipid Research

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Borage (Borago officinalis L.)

Tewari

Bawari

Patni

et al. 2019

Nonvitamin and Nonmineral Nutritional Supplements

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Myeloid atg5 deletion impairs n-3 PUFA-mediated atheroprotection

et al. 2020

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Background and aims: Dietary long-chain (≥ 20 carbons) n-3 polyunsaturated fatty acids (PUFAs) reduce atherosclerosis and enhance macrophage autophagy activation. How macrophage autophagy impacts atherosclerotic progression, particularly when comparing dietary n-3 PUFA supplementation vs. saturated fat feeding, is unknown. Methods:We generated myeloid-specific autophagy-deficient and control mice in the Ldlr −/− background by transplanting bone marrow from myeloid-specific autophagy-related (atg) 5 knockout mice and wild type controls into irradiated Ldlr −/− recipients. After 7 weeks for recovery from radiation, mice were fed an atherogenic diet containing 0.2% cholesterol and 20% calories as palm oil (PO diet), or 10% calories as PO plus 10% calories as fish oil (FO diet) for 16 weeks.Results: Compared to PO, FO significantly reduced plasma cholesterol, triglyceride, hepatic neutral lipid, and aortic caspase-1 cleavage, but increased aortic efferocytosis, leading to attenuated atherosclerosis in Ldlr −/− mice receiving wild type bone marrow. Myeloid atg5 deletion had little impact on plasma lipid concentrations and hepatic neutral lipid content, regardless of diet. Myeloid atg5 deletion increased aortic caspase-1 cleavage, decreased aortic efferocytosis and worsened atherosclerosis only in the FO-fed Ldlr −/− mice.

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Botanical oils enriched in n-6 and n-3 FADS2 products are equally effective in preventing atherosclerosis and fatty liver

Cited by 20 publications

References 71 publications

In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice

In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice

Borage (Borago officinalis L.)

Myeloid atg5 deletion impairs n-3 PUFA-mediated atheroprotection

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