New therapeutic strategies currently in development could inhibit the production of ceramides, a lipid molecule implicated in metabolic disease and long chain fatty acid oxidation disorders (LCFAOD).
Scott Summers, PhD, reviewed how an overaccumulation of fat-derived molecules, as seen in obesity, physical inactivity, and LCFAODs, contributes to the tissue dysfunction that underscores many common metabolic diseases, including diabetes. He presented this at the International Network for Fatty Acid Oxidation Research and Management (INFORM) Virtual Meeting on October 27-28, 2021.
From the Department of Nutrition and Integrative Physiology at the University of Utah in Salt Lake City, Dr. Summers stated that sphingolipids, a particular class of ceramide, might cause the most damage due to their ability to alter metabolic pathways and induce cellular apoptosis and fibrosis.
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As ceramide levels increase, “alterations in metabolism give way to a lipotoxic phase where the damage becomes irreversible,” Dr. Summers explained. This likely contributes to the end-organ damage seen in many metabolic diseases such as diabetic kidney disease, coronary artery disease (CAD), and nonalcoholic steatohepatitis (NASH).
Because of their strong association with metabolic disease, serum ceramide levels are also being utilized in the clinical setting as a marker of disease risk. Elevated ceramide levels confer a substantially increased risk of a major cardiac event within 1-5 years, Dr. Summers noted.
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Dr. Summers went on to describe how he and his team were able to disrupt ceramide production in knockout mice models by inhibiting a double bond in a particular enzyme integral to ceramide synthesis.
Even when on an obesogenic diet rich in saturated fats and sugar, mice with the inhibited enzyme showed an increased ability to clear glucose, Dr. Summers said. They also demonstrated decreased levels of liver fibrosis when compared to obese mice controls that had normal ceramide production.
Dr. Summers noted that inhibiting this enzyme, known as dihydroceramide desaturase-1 (DES1), could be an attractive target for a new class of therapeutics known as ceramide inhibitors.
Inhibiting ceramide-driven metabolic disease could potentially help treat fatty liver disease, improve glucose tolerance and insulin sensitivity, improve kidney function and prevent cytokine-induced pancreatic beta-cell death, among having other clinical applications.
“[The] bottom line is that ceramides are really relevant to the damage in a lot of organs that accompany obesity, lipodystrophy, and we think, fatty acid oxidation disorders,” Dr. Summers said.
Reference
Ceramides and the two phases of lipotoxicity. Presented at: International Network for Fatty Acid Oxidation Research and Management (INFORM) Virtual Meeting: October 28, 2021; Virtual.
