An enzyme that fine-tunes the structure of ceramide lipid molecules could represent a promising new target for metabolic disorders including prediabetes, diabetes, and heart disease, according to a University of Utah Health-led research team. The enzyme dihydroceramide desaturase1 (DES1) removes the final two hydrogen atoms from ceramides, which effectively adds a double bond into the backbone structure. Studies by the University of Utah Health researchers discovered that deleting or deactivating DES1 in experimental mice fed a high-fat diet (HFD) led to reduced ceramide production, and improved glucose tolerance and lipid metabolism, without changing the animals’ weight. The scientists say the study results point to a role for ceramides in metabolic health and in sensing nutrition.
“We have identified a potential therapeutic strategy that is remarkably effective, and underscores how complex biological systems can be deeply affected by a subtle change in chemistry,” said Scott Summers PhD, chair of nutrition and integrative physiology at the University of Utah Health, and who was co-senior author of the team’s published study in Science. “Our work shows that ceramides have an influential role in metabolic health. “We’re thinking of ceramides as the next cholesterol.” The team’s report is titled, “Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.”
Ceramides and dihydroceramides are products of fat and protein metabolism, which accumulate in obese and hyperlipidemic humans and non-human primates, the authors wrote. “These enigmatic lipids have been implicated in a wide range of cellular processes related to metabolism, growth, and survival.” Human studies have also linked serum and tissue levels of ceramides with obesity-related disorders including insulin resistance, type 2 diabetes, and cardiovascular events. “Indeed, some clinics have begun measuring serum ceramides as a measure of risk of cardiovascular disease.”
The structure of ceramides and dihydroceramides comprises a sphingoid backbone attached to a variable fatty acid side chain. Ceramides, but not the dihydroceramides, contain a double bond in the backbone that alters the biophysical properties of the molecules. Summers lab had previously found that reducing ceramides could reverse signs of diabetes and metabolic disease, but the heavy-handed approaches tested caused severe side effects. So this time the University of Utah Health-led team set out to investigate whether a more subtle change—manipulating the double bond—would impact on metabolic factors such as insulin resistance and hepatic steatosis.
To do this Summer’s lab engineered mice in which the gene encoding DES1, the enzyme responsible for inserting the double bond into ceramide molecules, could be switched off in adulthood and deactivated in various tissues, or just in liver or fat cells. Another research group headed by co-senior author David Kelley MD, formerly of Merck Research Laboratories, took a different approach, and delivered short hairpin RNAs (shRNA) into the animals’ livers, again to block production of DES1.
When adult mice with normal levels of DES1 were fed a HFD they rapidly became obese, and in parallel developed insulin resistance and fatty livers, which are both signs of metabolic disease. Mice in which either of the DES1-targeting approaches was used to reduce ceramide stayed obese, but their metabolic health improved. Fat accumulation in the liver was reversed, and the animals demonstrated better insulin and glucose control. “Gene depletion from either adipose tissue or the liver comparably improved glucose tolerance and decreased circulating levels of glucose (in fed and fasted mice), insulin, and fatty acids.” Injections of shRNAs into diet-induced obese mice to knockdown liver Degs1 also improved insulin sensitivity and glucose homeostasis without affecting bodyweight … “These findings from Degs1 knockout mice suggest that ceramides induce ‘selective’ insulin resistance, a term previously reported to describe a pre-diabetic condition characterized by defective insulin-action toward glucose metabolism.”
“Their weight didn’t change but the way they handled nutrients did,” said Summers. “The mice were fat but they were happy and healthy.” Additional studies showed that lowering ceramides before putting the mice on a high-fat diet prevented the animals from weight gain and insulin resistance.
The researchers also measured how ceramide affected metabolism, and found that the molecules trigger pathways that promote fat storage, but also impair cells’ ability to use glucose as fuel. The experiments implicated activation of the Akt/PKB pathway, which inhibits cells’ ability to synthesize and take up sugars from the bloodstream. The results also indicated that ceramides slow fatty acid turnover, partly by causing liver cells to increase fatty acid storage, and triggering adipose tissue to burn less fat. Promoting fat storage then increases the production of ceramides, which play an additional role in stiffening the cell membrane.
Combining all these functions points to an overall model in which, when food is plentiful and cells store fat, the increase in ceramide levels strengthens the cells’ outer membrane to prevent rupture. “Serving in this role is usually good but it can potentially be bad,” explained Trevor Tippetts, a graduate student in the Summers lab and co-lead author. Tippetts suggests that problems arise during obesity, when there are persistently high levels of ceramides. Summers’ team speculates that sustained impairment of metabolic homeostasis then leads to insulin resistance and fatty liver disease.
The results hint at ceramide’s normal role. “We think that ceramides evolved to become a nutritional sensor,” said University of Utah Health research assistant professor Bhagirath Chaurasia, PhD, who suggested that ceramides serve as a signal that aids the body’s coping mechanisms when the amount of fat being taken into cells is more than energetic needs, and exceeds storage capacity.
“We surmise that ceramides serve as gauges of free fatty acid (FFA) excess when the energetic needs of the tissue have been met and the storage capacity (i.e., triglyceride synthesis, pathway) is saturated,” the researchers suggested. “When this occurs, the excess fatty acids spillover into the sphingolipid synthesis pathway, producing ceramides and other sphingolipids that initiate cellular responses that prevent aberrant membrane dissolution by detergent-like FFAs.”
The potential benefits of lowering ceramides in humans isn’t yet known, but with evidence linking ceramides to metabolic disease, some clinics are carrying out ceramide screening tests as an indicator of cardiovascular disease risk. Summers and Kelley are developing drug inhibitors of DES1 as potential therapeutics.
“Collectively, our findings presented here indicate that ceramides contribute to metabolic disease, and may present an opportunity for clinical intervention,” the investigators stated. “These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.” And, as Kelley noted, “This project provides substantial validation that this is a discrete and highly effective point of intervention.”