December 16, 2024
Keio University School of Medicine
A group led by Assistant Professor Seong-Woon Ko (at the time of the research), Senior Lecturer Jun Anzai, and Professor Masaki Ieda from the Division of Cardiology, Department of Internal Medicine, Keio University School of Medicine, in collaboration with a group including Associate Professor Kenichiro Kinouchi and Professor Kaori Hayashi from the Department of Internal Medicine (Nephrology, Endocrinology, and Metabolism), Professor Kenji Tanaka from the Institute for Advanced Medical Research (Neuroscience), and Professor Tatsushi Onaka from Jichi Medical University, has discovered a new molecular mechanism by which social isolation reduces oxytocin secretion in the hypothalamus, leading to abnormal lipid metabolism in the liver and thereby promoting atherosclerosis. Although social isolation has been reported as a risk factor for ischemic cardiovascular diseases caused by dyslipidemia and atherosclerosis in humans, the detailed mechanism remained unclear. In this study, the research team conducted experiments specifically on sibling mice, which are known to form particularly strong "bonds" among social mice, to examine the effects of social isolation stress across multiple organs. The results showed that social isolation stress promotes atherosclerosis independently of previously presumed factors such as increased food intake and body weight, or activation of the sympathetic nervous system, the hypothalamic-pituitary-adrenal axis, and inflammation. The team also clarified that the mechanism involves the disruption of the lipid metabolism regulatory system mediated by oxytocin, which is produced in the hypothalamus and acts on hepatocytes. Detailed analysis revealed that oxytocin controls systemic lipid metabolism by performing two functions in hepatocytes: promoting cholesterol excretion through bile acid synthesis via CYP7A1, and breaking down triglycerides by regulating lipoprotein lipase (LPL) activity via ANGPTL4 and ANGPTL8. Furthermore, they confirmed that oral supplementation of oxytocin can suppress the dyslipidemia and atherosclerosis caused by social isolation.
Oxytocin is known as the "love hormone" and is involved in social behavior, emotional regulation, lactation, and uterine contraction. This study not only revealed a new function of oxytocin but also established it as a key molecule linking the brain and the liver. Currently, no therapeutic agents for dyslipidemia used in clinical practice have mechanisms that promote bile acid synthesis or improve LPL activity. These findings strongly suggest that oxytocin is a promising new therapeutic target for the progression of atherosclerosis, especially that caused by social isolation, and that social connections and "bonds" are crucial for preventing dyslipidemia, a cause of atherosclerosis.
These research findings were published in the journal Circulation Research on November 27, 2024 (US time).
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