Browsing by Author "Erbay, Ebru"

Now showing 1 - 7 of 7

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
ER Stress-induced sphingosine-1-phosphate lyase phosphorylation potentiates the mitochondrial unfolded protein response
(American Society for Biochemistry and Molecular Biology Inc., 2022-10) Yıldırım, Aslı Dilber; Citir, Mevlut; Doğan, Aslı Ekin; Veli, Zehra; Yıldırım, Zehra; Tufanli, Ozlem; Traynor-Kaplan, Alexis; Schultz, Carsten; Erbay, Ebru
The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1’s kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL’s enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR–like ER kinase upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of ER and mitochondria to ER stress in mammalian cells. © 2022 THE AUTHORS.
Open Access
ER-mitochondrial communication gets stressful
(American Association for the Advancement of Science, 2014) Erbay, Ebru
Open Access
Inflammatory causes of obesity and metabolic diseases
(CRC Press, 2014) Erbay, Ebru; Hotamışlıgil, G. S.; Claude, B.; Bray, G. A.
Open Access
Intercepting the lipid-induced integrated stress response reduces atherosclerosis
(Elsevier, 2019) Onat, Umut I.; Yıldırım, Aslı D.; Tufanlı, Özlem; Çimen, İsmail; Kocatürk, Begüm; Veli, Zehra; Hamid, S.; Shimada, K.; Chen, S.; Sin, J.; Shah, P.; Gottlieb, R.; Arditi, M.; Erbay, Ebru
Background Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma. Objectives Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis. Methods The authors investigated ISR’s role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes. Results The results show lipid-activated eIF2α signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1β secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis. Conclusions These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1β secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles’ responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis.
Open Access
PACT establishes a posttranscriptional brake on mitochondrial biogenesis by promoting the maturation of miR-181c
(American Society for Biochemistry and Molecular Biology Inc., 2022-07) Doğan, Aslı Ekin; Hamid, Syed M.; Yıldırım, Aslı Dilber; Yıldırım, Zehra; Sen, Ganes; Riera, Celine E.; Gottlieb, Roberta A.; Erbay, Ebru
The double-stranded RNA-dependent protein kinase activating protein (PACT), an RNA-binding protein that is part of the RNA-induced silencing complex, plays a key role in miR-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RNA-induced silencing complex, and determines proper miR length. Apart from PACT's role in mediating the antiviral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a posttranscriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial complex IV subunit I (Mtco1) and sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT. © 2022 The Authors
Open Access
RAW264.7 makrofajlarında lipotoksik endoplazmik retikulum stres sürecinde ifadesi değişen mikroRNAların tanımlanması
(Türk Biyokimya Derneği, 2016) Nadir, M.; Tufanlı, Özlem; Erbay, Ebru; Atalay, A.
Amaç: Kan dolaşımındaki serbest yağ asitlerinin artışı ve adipoz olmayan dokulardaki birikimi, insülin direnci, diyabet ve ateroskleroz gibi obezite ile ilişkili metabolik ve emflamatuvar hastalıkların gelişiminde önemli rol oynar. Yağ dokusu, fazla olan yağ asidini depolayabilme kabiliyetine sahipken, diğer dokulara ulaşan fazla miktarda yağ asidi, endoplazmik retikulum (ER) ve mitokondri gibi intraselüler metabolik organelleri zorlayarak stres cevabının oluşmasına ve lipotoksik hücre ölümüne neden olur. Katlanmamış protein yanıtı (KPY) endoplazmik retikulumun strese karşı önemli bir adaptasyonudur. Lipidler ile KPY arasındaki ilişkinin nasıl olduğu ve katlanmamış protein yanıtı ile adaptif ve destrüktif sonuçların nasıl yönetildiği halen tam olarak aydınlatılamamıştır. miRNA biyogenezinde KPY'nın rolünün yanı sıra, katlanmamış protein yanıtını düzenleyen miRNAların önemine işaret eden kanıtlar bulunmaktadır. Bu çalışmada lipidler ile KPY arasındaki ilişkiyi anlamak için, makrofajlardaki lipotoksik ER stresi sürecinde düzenlenen mikroRNA'ların tanımlanması amaçlanmıştır.Metod: Fare makrofaj hücre hattına (RAW 264.7), serbest yağ asidi olan 500 µM palmitat -obez hastaların kan dolaşımındaki seviyede- uygulanarak stres oluşturulmuştur. miRBase sürüm 16'daki bilinen tüm fare mikroRNAlarını içeren QRT-PCR temelli miSCRİPT miRNA PCR array sistemi kullanılarak, hücrelerdeki tüm mikroRNAom profili analiz edilmiş ve potansiyel hedefler için yolak analizleri gerçekleştirilmiştir.Bulgular: Lipotoksik ER stres sonucu, 227 mikroRNA'nın ifade seviyesi 2 kat üzerinde değişmiş ve 43'ü 2 kattan fazla,13'ü ise 3-24 kat değişim göstermiştir. Yolak analizi gerçekleştirilerek lipotoksik ER stresi ile ilişkili mikroRNA'ların mRNA hedefleri belirlenmiş ve gruplanmıştır.Sonuç: Makrofajlar, ER stresini indükleyebilen yüksek konsantrasyondaki doymuş yağ asidine maruz bırakıldığında mikroRNAome profillerinde dinamik bir değişim gözlenmektedir. Bulgularımız, obezitedeki doku ilişkili makrofajlar ve kan dolaşımındaki monositlerdeki lipotoksik stres sonuçlarını yansıtmaktadır. Detaylı çalışmalar gerçekleştirilerek, lipotoksik ER stresi sürecinde ifadesinin değiştiğini rapor ettiğimiz mikroRNA değişimlerinden hangi KPY yolağının sorumlu olduğu belirlenebilir.