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.”