Northwestern Medicine investigators have discovered a potential wide-ranging therapeutic target for preventing and treating the metabolic syndrome, a common cluster of conditions that increases the risk of heart disease, stroke and diabetes, according to findings published in Scientific Reports.
The investigators, led by Douglas Vaughan, MD, chair and the Irving S. Cutter Professor of Medicine, found that administering a new drug that blocks the activity of the protein PAI-1 directly impacts liver lipid metabolism and may help prevent the development of the syndrome, which currently affects one in three Americans and millions worldwide.
“Here’s one singular factor that we could potentially target, and by doing so, prevent the metabolic syndrome itself, as well as the cardiovascular morbidity and mortality that’s associated with the syndrome,” Vaughan said.
Plasminogen activator inhibitor 1, or PAI-1, is a protein found in the blood and increased levels can cause clotting in arteries, contributing to damage in the lungs, heart, kidneys and brain.
Previous studies have demonstrated that PAI-1 is an important mechanistic contributor to several components of the metabolic syndrome, including obesity, high blood pressure and insulin resistance. But the direct link between increased PAI-1 and impaired lipid metabolism had remained unknown.
For the current study, Vaughan and colleagues used RNA sequencing and gene expression analysis techniques to analyze liver mRNA in mouse models of metabolic syndrome. One group was treated with a PAI-1 inhibitor drug and the other served as controls.
In mice that received the drug, investigators found that the PAI-1 inhibitor drug regulated liver lipid metabolism, specifically by reducing the expression of PCSK9 and increasing the expression of FGF21. Notably, drugs that block the production or function of PCSK9 are effective in reducing cardiovascular disease, while there is increased interest in developing FGF21-targeting drugs to prevent and treat obesity-related metabolic complications, according to Vaughan.
By lowering PAI-1 levels both genetically and pharmacologically, overall liver lipid metabolism improved, providing a dual benefit in addressing the metabolic consequences of obesity.
“This is a singular factor that seems to pull it all together in a way that provides some explanation as to why these characteristics travel in a group,” Vaughan said. “It’s almost like a polypill, but instead here is one target that has all these really remarkable physiological effects. This is an opportunity to develop a breakthrough via a pharmacologic ‘twofer’.”
As for next steps, Vaughan said the team hopes to determine the intracellular mechanisms involved in PAI-1 signaling the liver to alter lipid metabolism and begin the process with the Food and Drug Administration to secure an Investigational New Drug (IND) application to test the metabolic benefits of the drug in humans.
The current findings build off previous work from the Vaughan laboratory regarding the biological effects of PAI-1. That study involved a Swiss Amish community in Indiana with a mutation in the gene that codes for PAI-1 and found that lower levels of the protein protected against the development of diabetes, improved insulin sensitivity and protected against the biological manifestations of aging.
Because two of the most important risk factors for poor outcomes in patients with COVID-19 include age and obesity, Vaughan and fellow Feinberg investigators are currently testing whether the same PAI-1 inhibitor drug can reduce morbidity and mortality in high-risk patients with COVID-19.
Co-authors include Joshua Levine, MD, PhD, a former medicine resident at McGaw Medical Center, Mesut Eren, PhD, research associate professor of Medicine in the Division of Cardiology; Sadiya Khan, ’09 MD, ’14 MS, ’10, ’12 GME, assistant professor of Medicine in the Division of Cardiology and of Preventive Medicine in the Division of Epidemiology; Sanjiv Shah, ’00 MD, Neil J. Stone, MD, Professor of Cardiology; and Grant Barish, MD, associate professor of Medicine in the Division of Endocrinology.
This work was supported by the Endocrine Fellows Foundation, the Irving S. Cutter Endowment; the American Heart Association grant 15CVGPSD2726014; the National Institutes of Health grant RO1HL51387, RO1HL142761, RO1HL136373 and RO1HL132985; and the National Institute of Diabetes and Digestive and Kidney Diseases award T32DK007169.