Double bond configuration of palmitoleate is critical for atheroprotection

Ismail Cimen; Zehra Yildirim; Asli Ekin Dogan; Asli Dilber Yildirim; Ozlem Tufanli; Umut Inci Onat; UyenThao Nguyen; Steven M Watkins; Christian Weber; Ebru Erbay

doi:10.1016/j.molmet.2019.08.004

Double bond configuration of palmitoleate is critical for atheroprotection

Mol Metab. 2019 Oct:28:58-72. doi: 10.1016/j.molmet.2019.08.004. Epub 2019 Aug 7.

Authors

Affiliations

¹ Institute for Cardiovascular Prevention, LMU Munich, German Cardiovascular Research Centre (DZHK), Partner Site Munich Heart Alliance Munich, 80336, Germany.
² Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey; National Nanotechnology Center, Bilkent University, Ankara, 06800, Turkey; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
³ New York University, Lagone Medical Center, New York, NY 10016, USA.
⁴ Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey; National Nanotechnology Center, Bilkent University, Ankara, 06800, Turkey.
⁵ Metabolon, Morrisville, NC, 27560, USA.
⁶ Verso Biosciences, San Francisco, CA, 94124, USA.
⁷ Institute for Cardiovascular Prevention, LMU Munich, German Cardiovascular Research Centre (DZHK), Partner Site Munich Heart Alliance Munich, 80336, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
⁸ Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey; National Nanotechnology Center, Bilkent University, Ankara, 06800, Turkey; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. Electronic address: ebru.erbay@cshs.org.

Abstract

Objective: Saturated and trans fat consumption is associated with increased cardiovascular disease (CVD) risk. Current dietary guidelines recommend low fat and significantly reduced trans fat intake. Full fat dairy can worsen dyslipidemia, but recent epidemiological studies show full-fat dairy consumption may reduce diabetes and CVD risk. This dairy paradox prompted a reassessment of the dietary guidelines. The beneficial metabolic effects in dairy have been claimed for a ruminant-derived, trans fatty acid, trans-C16:1n-7 or trans-palmitoleate (trans-PAO). A close relative, cis-PAO, is produced by de novo lipogenesis and mediates inter-organ crosstalk, improving insulin-sensitivity and alleviating atherosclerosis in mice. These findings suggest trans-PAO may be a useful substitute for full fat dairy, but a metabolic function for trans-PAO has not been shown to date.

Methods: Using lipidomics, we directly investigated trans-PAO's impact on plasma and tissue lipid profiles in a hypercholesterolemic atherosclerosis mouse model. Furthermore, we investigated trans-PAO's impact on hyperlipidemia-induced inflammation and atherosclerosis progression in these mice.

Results: Oral trans-PAO supplementation led to significant incorporation of trans-PAO into major lipid species in plasma and tissues. Unlike cis-PAO, however, trans-PAO did not prevent organelle stress and inflammation in macrophages or atherosclerosis progression in mice.

Conclusions: A significant, inverse correlation between circulating trans-PAO levels and diabetes incidence and cardiovascular mortality has been reported. Our findings show that trans-PAO can incorporate efficiently into the same pools that its cis counterpart is known to incorporate into. However, we found trans-PAO's anti-inflammatory and anti-atherosclerotic effects are muted due to its different structure from cis-PAO.

Keywords: Atherosclerosis; Inflammasome; Lipid-induced inflammation; Lipokines; Organelle stress; Palmitoleate; Ruminant trans-fatty acids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis / metabolism
Atherosclerosis / pathology
Atherosclerosis / prevention & control*
Cells, Cultured
Fatty Acids, Monounsaturated / chemistry*
Fatty Acids, Monounsaturated / pharmacology*
Male
Mice
Mice, Knockout

Substances

Fatty Acids, Monounsaturated
palmitoleic acid

Grants and funding

692511/ERC_/European Research Council/International