Cholesterol is often blamed for causing heart disease, but it is not the only troublesome lipid.
Triglycerides are fats that cells use as fuel. They are transported to cells via the bloodstream, but when triglyceride levels are high, excessive numbers of the fat particles are forced into cells lining the arteries. That causes inflammation in cholesterol-laden plaques in the arteries and may explain why people with high triglyceride levels have an increased risk of cardiovascular disease.
But unlike cholesterol, which can be lowered with statins, drugs that reduce triglyceride levels are not very effective, and results on heart disease outcomes are mixed.
Now new research from the lab of Utpal Pajvani, MD, PhD, has revealed a possible strategy to lowering triglycerides: In mouse studies, researchers show that inhibiting an enzyme in the liver significantly reduces triglyceride levels.
The research was published online March 22 in Cell Metabolism.
Gamma Secretase Inhibitors Reduce Triglyceride Levels
The enzyme, called gamma secretase, has multiple functions throughout the body.
Previous studies by Pajvani and his colleagues demonstrated that inhibiting the enzyme with certain drugs improves blood sugar levels and insulin sensitivity while reducing fat accumulation and inflammation in the liver.
In the new study, Pajvani’s team—led by the study’s first author KyeongJin Kim, PhD—found that inhibiting the enzyme also causes liver cells to pull triglycerides out of the bloodstream.
“We see this data as proof of principle that a drug that inhibits gamma secretase could be used to produce multiple benefits at once,” said Pajvani, adding that the liver cells seem unaffected by the increased intake. “This approach would be especially beneficial for people with type 2 diabetes, who have insulin resistance and high blood sugars but often also have high levels of plasma triglycerides and fatty liver disease.”
“Antisense” Molecule Can Prevent Side Effects of Current Inhibitors
Current drugs that inhibit gamma secretase block the enzyme throughout the body and cause severe gastrointestinal side effects, precluding them from being used to prevent or treat chronic diseases.
To address this problem, Pajvani’s team collaborated with industry colleagues to develop an “antisense” molecule that preferentially blocks gamma secretase in the liver. In a series of mouse experiments, they found that the molecule reduced triglycerides and glucose in the blood, without apparent side effects.
But he cautions that there are years of work ahead before the compound or a similar drug would be available for testing in people.
“Many people are looking at new ways to reduce triglycerides,” Pajvani said, “and the more possibilities we identify, the greater chance we have of ultimately succeeding.”
Utpal Pajvani is a Herbert Irving Assistant Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons and a member of the Naomi Berrie Diabetes Center at Columbia University Irving Medical Center.
KyeongJin Kim is an associate research scientist in the Department of Medicine, Vagelos College of Physicians and Surgeons.
The title of the paper is “Gamma-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor.”
The other authors on this international collaboration are Enrico Bertaggia, Samuel Lee, Li Qiang, Rebecca A. Haeusler, and Henry N. Ginsberg (all from CUIMC); Ira J. Goldberg (New York University); Mark J. Graham (Ionis Pharmaceuticals); Meenakshi Sundaram and Zemin Yao (University of Ottawa); and Daniel Metzger and Pierre Chambon (Institut de Génétique et de Biologie Moléculaire et Cellulaire, France).
This work was supported by the National Institutes of Health (grants DK103818, HL46095, HL92969, and HL125649), an Edward Mallinckrodt, Jr. Foundation Grant, a Paul Marks Scholarship, the Canadian Institutes of Health Research (grant #MOP123279), and an AHA Scientist Development Grant (17SDG33660031).
The authors declare that they have no competing financial interest in the work described, but Utpal Pajvani is an inventor of a patent held by Columbia University related to this work.