Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation.
De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue. We show that PAO treatment evokes an overall lipidomic remodeling of the endoplasmic reticulum (ER) membranes in macrophages and mouse tissues, which is associated with resistance of the ER to hyperlipidemic stress. By preventing ER stress, PAO blocks lipid-induced inflammasome activation in mouse and human macrophages. Chronic PAO supplementation also lowers systemic interleukin-1β (IL-1β) and IL-18 concentrations in vivo in hyperlipidemic mice. Moreover, PAO prevents macrophage ER stress and IL-1β production in atherosclerotic plaques in vivo, resulting in a marked reduction in plaque macrophages and protection against atherosclerosis in mice. These findings demonstrate that oral supplementation with a product of DNL such as PAO can promote membrane remodeling associated with metabolic resilience of intracellular organelles to lipid stress and limit the progression of atherosclerosis. These findings support therapeutic PAO supplementation as a potential preventive approach against complex metabolic and inflammatory diseases such as atherosclerosis, which warrants further studies in humans.
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey. National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey.
Ismail
I
Çimen
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey. National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey.
Begüm
B
Kocatürk
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
Seda
S
Koyuncu
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey. National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey.
Özlem
Ö
Tufanlı
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey. National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey.
Umut I
UI
Onat
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey. National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey.
Asli D
AD
Yıldırım
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey. National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey.
Onur
O
Apaydın
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
Şeyma
Ş
Demirsoy
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
Zaliha G
ZG
Aykut
Metabolon, Sacramento, CA 95691, USA.
Uyen T
UT
Nguyen
Metabolon, Sacramento, CA 95691, USA.
Steven M
SM
Watkins
Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Gökhan S
GS
Hotamışlıgil
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey. National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey. eerbay@bilkent.edu.tr.
Ebru
E
Erbay
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use*; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008055:Lipids; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000473:pathology
D001057:Apolipoproteins E; D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D058847:Inflammasomes; D018836:Inflammation Mediators; D008055:Lipids; C008757:palmitoleic acid