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The Bacterial Serine Dipeptide Lipid, Lipid 654, Attenuates Atherosclerosis Development in LDL‐Receptor Knockout Mice Fed a Western‐Type Diet
Author(s) -
Garcia Chelsea,
Millar Courtney L.,
Anto Liya,
Nichols Frank C.,
Blesso Christopher N.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03567
Subject(s) - endocrinology , medicine , ldl receptor , chemistry , cholesterol , receptor , lipoprotein , biology
Bacteroidetes of the oral and gut microbiome produce serine‐glycine dipeptide lipids that activate Toll‐like receptor 2. Lipid 654 (L654), a major serine dipeptide lipid class, has been detected in serum, brain, and carotid arteries of humans. We investigated the effects of L654 on atherosclerosis development in male low‐density lipoprotein receptor knockout (LDLr −/− ) mice fed a high‐sucrose, Western‐type diet (HFD; 21% milk fat, 0.2% cholesterol, 34% sucrose by weight). Mice were fed either a standard chow diet (n = 9) or HFD (n = 30) for 14 weeks. During the last 7 weeks of the HFD, mice were intraperitoneal‐injected 3 times per week with either 1 μg of L654 (HFD‐L654, n = 15) or vehicle (HFD‐Veh, n = 15). L654 was detected in mouse feces and liver by UPLC‐MS/MS. Compared to chow‐fed mice, mice fed HFD had lower fecal Bacteroidetes relative abundance (−28%) and fecal L654 concentrations (−82%). In the context of HFD, L654 had a hypocholesterolemic effect with HFD‐L654 having significantly lower cholesterol concentrations in both serum (−24%) and liver (−35%) compared to HFD‐Veh. L654 also reduced hepatic inflammation, as HFD‐L654 had lower serum ALT (−43%) and hepatic pro‐inflammatory gene expression (~30–45% lower) compared to HFD‐Veh. Finally, L654 attenuated atherosclerosis, as HFD‐L654 had significantly lower aortic root lesion size (−39%) compared to HFD‐Veh. In summary, a Western‐type diet markedly lowered fecal L654 concentrations in LDLr −/− mice. Chronic L654 administration protected against several metabolic defects induced by Western‐type diet, including hyperlipidemia, liver inflammation, and atherosclerosis development. Further studies are warranted to assess the underlying metabolic effects of these unique class of bacterial lipids.