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6 results on '"Kocaturk, Begum"'

1. Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Author

Tufanli, Ozlem, Telkoparan Akillilar, Pelin, Acosta-Alvear, Diego, Kocaturk, Begum, Onat, Umut Inci, Hamid, Syed Muhammad, Çimen, Ismail, Walter, Peter, Weber, Christian, and Erbay, Ebru

Subjects
Atherosclerosis, Aging, Cardiovascular, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Animals, Apolipoproteins E, Cells, Cultured, Disease Progression, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Homeostasis, Inflammasomes, Interleukin-18, Interleukin-1beta, Macrophages, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Protein Serine-Threonine Kinases, Signal Transduction, Small Molecule Libraries, Unfolded Protein Response, endoplasmic reticulum stress, unfolded protein response, metaflammation, lipotoxicity, atherosclerosis
Abstract

Metaflammation, an atypical, metabolically induced, chronic low-grade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ER-resident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.

Published
2017

6. Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation

Author

Cimen, Ismail, Kocaturk, Begum, Koyuncu, Seda, Tufanli, Ozlem, Onat, Umut I., Yildirim, Asli D., Apaydin, Onur, Demirsoy, Seyma, Aykut, Zaliha G., Nguyen, Uyen T., Watkins, Steven M., Hotamisligil, Goekhan S., Erbay, Ebru, Cimen, Ismail, Kocaturk, Begum, Koyuncu, Seda, Tufanli, Ozlem, Onat, Umut I., Yildirim, Asli D., Apaydin, Onur, Demirsoy, Seyma, Aykut, Zaliha G., Nguyen, Uyen T., Watkins, Steven M., Hotamisligil, Goekhan S., and Erbay, Ebru

Abstract

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-1 beta (IL-1 beta) and IL-18 concentrations in vivo in hyperlipidemic mice. Moreover, PAO prevents macrophage ER stress and IL-1 beta 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.

Published
2016

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