Browsing by Author "Onat, Umut İnci"

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Open Access
Double bond configuration of palmitoleate is critical for atheroprotection
(Elsevier, 2019) Çimen, I.; Yıldırım, Zehra; Doğan, Aslı Ekin; Yıldırım, Aslı Dilber; Tufanlı, Ö.; Onat, Umut İnci; Nguyen, U.; Watkins, S.; Weber, C.; Erbay, Ebru
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.
Open Access
The role of lipid-induced integrated stress response in metaflammation and atherosclerosis
(2019-07) Onat, Umut İnci
Chronic inflammation resulting from metabolic overloading of organelles (such as the endoplasmic reticulum (ER) and mitochondria that control cellular homeostasis) is a major cause of metabolic disorders including diabetes, obesity and atherosclerosis. ER is an organelle that plays a critical role in cellular metabolism through biosynthesis of lipids, protein maturation and secretion, and calcium storage. Furthermore, a stressed endoplasmic reticulum maintains cellular homeostasis by initiating a conserved stress response pathway that is known as Unfolded protein response (UPR). UPR is activated in response to diverse stimuli that disrupts ER functions and serves asva pro-survival mechanism to regain ER homeostasis. However, in prolonged or severe ER stress, chronic UPR can promote inflammation and apoptosis. Activated UPR, inflammation and necrosis are observed in and causally associated with atherosclerosis. UPR has three branches, one of which is initiated by the protein kinase RNA (PKR) like ER kinase (PERK) and signals to eukaryotic initiation factor 2a (eIF2a). This signaling arm of the UPR is also part of a larger, translational control pathway known as the integrated stress response (ISR). Activation of ISR has been observed in atherosclerosis and could promote atherosclerosis To study the contribution of ISR to atherogenesis, I took advantage of three small molecule inhibitors that can modulate this pathway. I also used a chemical-genetic approach, known as the Adenosine triphosphate (ATP) analog sensitive kinase (ASKA) technology, to interrupt PERK kinase activity. With these multiple tools, I was able to specifically interfere with ISR signaling at multiple molecular nodes in order to study the role of lipid-induced ISR in inflammation, inflammasome activation and atherosclerosis. I discovered that during lipid-induced ER stress, PERK to Activating transcription factor 4 (ATF4) signaling resulted in transcriptional induction of a mitochondrial protease, Lon protease 1 (LONP1), which degrades PTEN induced putative kinase 1 (PINK1) and blocks Parkin-mediated mitochondria clearance (or mitophagy). This in turn causes an increase in mitochondrial reactive oxygen species (ROS) production, inflammasome activation and pro-inflammatory cytokine secretion such as interleukin-1b (IL-1b) in both mouse and human macrophages. I also discovered that these inhibitors are also effective in reducing hyperlipidemia-induced inflammasome activation in Apolipoprotein E-deficient (Apoe/- ) mice and consequently, in preventing atherosclerosis progression. These results point out that intercepting with ISR signaling in hypercholestrolemia can be considered as a novel therapeutic approach that could be developed against atherosclerosis.