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

A significant reduction in cardiovascular disease risk can be achieved by replacing saturated fatty acids with mono- or poly-unsaturated fatty acids. Palmitoleate is a mono-unsaturated fatty acid that has beneficial effects on metabolism and atherosclerosis. However, it is unknown whether the cis and trans isoforms of palmitoleate have the same effect. Cimen and colleagues directly compared the effects of cis- and trans-palmitoleate on inflammation and atherosclerosis in a hypercholesterolemic mouse model and found that positive effects were restricted to the cis form only.

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.