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Fat pathway clarified

PGC-1beta is a key link between fatty diets and serum triglyceride and cholesterol levels

By | January 31, 2005

Researchers reported in Cell last week (January 28) that they have uncovered a mechanism by which high-fat diets translate into high blood levels of triglycerides and cholesterol. The mechanism involves coactivator PGC-1β, which has not previously been implicated in lipid metabolism.

The team studied changes in gene expression in mice fed a diet high in trans-fats and saturated fats. "We found that PGC-1β is elevated by dietary saturated and trans-fats, and coactivates several transcription factors," senior author Bruce Spiegelman of Harvard University told The Scientist.

The researchers found that PGC-1β forms a complex with the protein SREBP, Spiegelman said. "This increases SREBP activity on genes involved in fatty acid and cholesterol synthesis."

David Mangelsdorf of Howard Hughes Medical Institute, who was not involved in this study, said the investigators had identified one of the key players in the pathway that leads to the synthesis and secretion of triglycerides and cholesterol.

In addition to SREBP, that pathway involves LXR, a transcription factor that senses high levels of fat. LXR binds sterols in the nucleus of liver cells, and thus activated allows the activation of SREBP1, which in turn induces genes involved in fatty acid and cholesterol synthesis. Both LXR and SREBP1 need coactivators to be able to work on the genes they activate. Now it is clear that PGC-1β is one of those coactivators, Mangelsdorf explained.

"Before, we only knew that PGC-1β had a function in mitochondrial oxidation," said Pere Puigerver of Johns Hopkins University, who did not participate in the study. "Now, we have a connection between a nutrient, a lipid pathway that senses saturated fats, and the induction of lipogenesis in the liver, and secretion and transport of lipoproteins. These lipoproteins lead to high blood levels of cholesterol and triglycerides." The paper suggests to Puigserver that PGC-1β somehow acts as a sensor for saturated fats.

But Mangelsdorf disagrees. "I think that calling PGC-1β a sensor is a misnomer," he said, suggesting that PGC-1β is actually interpreting signals from other sensors. "Nuclear receptors, such as LXR, which bind to lipids, act more as sensors." For PGC-1β, it is not clear yet how it is activated or what controls its expression, he said.

Spiegelman's team also found that PGC-1β coordinates the secretion of lipoproteins and increases circulating triglycerides and cholesterol, while reducing fat accumulation in the liver. These findings surprised Mangelsdorf.

"Reduced fat in the liver is not what you get when you feed a normal animal a high-fat diet," Mangelsdorf said. "The first sign of syndrome X [a cluster of risk factors contributing to the development of cardiovascular disease] in humans is a fatty liver."

Joyce Repa, of the University of Texas, said the findings will open up new areas of investigation. "Until now, PGC-1β has been neglected," she said. "This study, which is linked to triglyceride homeostasis, will get the field relatively excited about looking at other effects of this coactivator protein."

Repa hopes to see this research, which was based on 1 or 2 days' dietary exposure, extended to more chronic conditions. "This study was appropriate for the types of questions the researchers were asking, but most people's diets are not high in fat like this."

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