With Just One Enzyme Missing, Mice Show 'Global' Metabolic Improvements

When researchers created mice lacking an enzyme that breaks down and releases stored triglycerides (more properly known as triacylglycerols or TGs), they expected to see animals with better lipid profiles. But according to a report in the March Cell Metabolism, a Cell Press publication, they got more than they bargained for. The triacylglycerol hydrolase (TGH)-deficient mice showed global metabolic benefits, with essentially no downside.

"It was a surprising and unexpected finding," said Richard Lehner of the University of Alberta. "With this gene deleted, not only was there a decline in very low-density lipoproteins in the whole mouse, it also affected metabolism in fat tissue. The insulin-secreting cells became smaller, suggesting that they didn't have to work as hard to secrete insulin, and the mice became more insulin sensitive." The animals ate more, but they also expended more energy and showed no change in body weight.

Very low-density lipoproteins (VLDLs) are a form of "bad" cholesterol, Lehner explained. TGH normally frees up triglycerides from their storage place in the liver, releasing them for assembly into VLDLs. Therefore, one might expect that loss of TGH would have ill effects on the liver, as triglycerides would build up there. Indeed, he says, similar experiments with other enzymes have shown such an effect.

"We didn't observe that here," Lehner said. "Instead of being stored in liver, triglycerides were directed for oxidation." In other words, they were burned. The liver also compensated by synthesizing less fat.

The studies demonstrate the potential of TGH as a therapeutic target for lowering blood lipid levels, with possible far-reaching beneficial side effects throughout the body. That may be especially worthy of note, given that drug companies already have a TGH blocker. In fact, Lehner's team earlier showed that the TGH-inhibiting drug can lower the secretion of VLDLs from liver cells. But it wasn't clear whether the drug was really acting only on TGH. The new findings add support to the notion that loss of TGH activity alone can have very significant and positive effects...