The role of LPCAT3 in pathogenesis of diabetic cardiomyopathy

University Of Nebraska Lincoln, Lincoln NE

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Abstract

Cardiovascular diseases are the number one cause of death globally. Most CVDs are caused by risk factors such as tobacco use, hypertension, obesity or diabetes. Diabetic cardiomyopathy (DC) is characterized by abnormal cardiac structure and function in the absence of other cardiac risk factors and is often undiagnosed in patients with diabetes mellitus. Untreated, this condition increases the chance of heart failure at least 2.4-fold in men and 5.1-fold in women compared to individuals without diabetes. Despite the increase in the number of cases in the past several decades, the underlying molecular mechanisms of DC pathogenesis remain poorly understood, thereby preventing the development of effective diagnostic tools and pharmacotherapies as well as preventive strategies. One of the emerging hypothesis is that altered membrane polyunsaturated fatty acid composition can activate ER stress signaling, oxidative stress and inflammation in cells. It has been speculated that increased membrane phospholipid saturation may be an underlying cause of many metabolic disorders. Lysophosphatidylcholine acyltransferase 3 (LPCAT3) is a major cardiac enzyme that catalyzes the formation of phosphatidylcholine (PC) from lysophosphatidylcholine. LPCAT3 preferentially synthesizes PC containing unsaturated fatty acids at the sn-2 position. A recent study has shown that LPCAT3 overexpression in livers of obese diabetic db/db mice effectively reduced ER stress by modulating PC saturation. However, the role of LPCAT3 in cardiac metabolism is very poorly understood. Therefore, the proposed project aims at establishing the role of LPCAT3 in cardiac function and investigating the effect that LPCAT3 deficiency may play in development of DC. Additionally, the project will investigate the potential of PC supplemented diet to improve cardiac function in obese mice. Finally, the proposed study will investigate the potential of LPCAT3 overexpression through its transcription factor - liver X receptor (LXR) activation on improving cardiomyocyte structure and function in acute lipotoxicity.