Clusterin linked to both cardiac and metabolic diseases

Scientists have linked the protein clusterin to a number of different cardiometabolic syndrome risks, by identifying its actions in the liver.

Researchers at The Ohio State University College of Medicine, Houston Methodist Research Institute and Houston Methodist Cancer Center spent nearly a decade studying this process.

Cardiometabolic syndrome (CMS) is a combination of various metabolic dysfunctions that are categorised as impaired glucose tolerance, insulin resistance, hypertension, dyslipidemia and central adiposity. These risks are enhanced for those who smoke or are physically inactive.

The extracellular matrix protein clusterin is overproduced from the fat cells of obese patients, and is strongly linked to type 2 diabetes, cardiovascular disease, mortality, high blood pressure and fatty liver disease.

The research team performed gene expression correlation analysis and blood measurements in 54 obese and 18 lean patients that were due to undergo elective surgery. The team also analysed human cell cultures, and mice that were prone to develop obesity-associated complications.

“Our goal was to discover new factors produced by the cells in fat tissue that have an impact on cardiometabolic disease. In particular, we wanted to identify those important to maintaining the framework of fat tissue, called the extracellular matrix, which becomes dysfunctional in obesity,” said first author Dr David Bradley, Assistant Professor in the Division of Endocrinology, Diabetes and Metabolism at The Ohio State University Wexner Medical Center and a member of Ohio State’s Diabetes and Metabolism Research Center.

CMS affects around 25 percent of the world’s population, and is recognised by the American Society of Endocrinology and the World Health Organization as a disease entity. Individuals affected by CMS are three times more likely to have a stroke or heart attack and two times more likely to die from coronary heart disease, than those who are not affected.

“This collaborative research is shedding new light on the importance of clusterin on ‘cardiometabolic syndrome’, which may eventually lead to developing new treatments for this life-threatening combination of diabetes, high blood pressure and obesity,” said Dr Craig Kent, Dean of the Ohio State College of Medicine. “Previously this protein clusterin has been mostly studied for its role in neurodegenerative diseases such as Alzheimer’s but it now appears to have a broader role in human physiology and disease.”

“This study shows the hypothesis generation power of emerging systems biology approaches in discovering novel targets and mechanisms on complex diseases such as CMS. The clusterin protein is a key component of the extracellular matrix, so this work opens up a new vista to understand the role of clusterin in inter-cellular crosstalk of tissue microenvironments of various diseases, including diabetes, cancer and neurodegeneration,” said the co-corresponding author, Dr Stephen Wong, Professor and Chair of the Department of Systems Medicine and Bioengineering at Houston Methodist.

“A critical issue has been to identify a unifying mechanism for components of cardiometabolic syndrome, ” said lead researcher Dr Willa Hsueh, Director of the Diabetes and Metabolism Research Center and Professor of Medicine in the Division of Endocrinology, Diabetes, and Metabolism at Ohio State’s Wexner Medical Center.

“Fat cells increase clusterin production as they enlarge in obesity. Clusterin may be a biomarker of disease, as well as a therapeutic target to potentially prevent this disease.”

The research team mentioned how further research involving mouse models is necessary in order to learn more about the impact of clusterin on each of the CMS components. The team also look to identify whether administrating clusterin-inhibiting antibodies inhibits CMS.

The study was published in the journal Diabetes Care.