Science Editor

With the economy in the tank and prices sky-high, even transcription factors are taking on second jobs.

In the June 13, 2008 issue of Science, researchers report that the transcription factor XBP1, which regulates protein synthesis and stress responses in secretory cells, is important for lipid synthesis in the liver.

XBP1 had originally been discovered by senior author Laurie Glimcher as a regulator of genes in the major histocompatiblity complex. It is also known to regulate the unfolded protein response, "an adaptive mechanism used by many different cells to handle the load of proteins in the endoplasmic reticulum," Glimcher, a professor at the Harvard School of Public Health, told BioWorld Today.

XBP1 is a required transcription factor during development, playing an important role in the liver prenatally. Mice lacking XBP1 do not survive to birth. Working under the assumption that a protein that is important during embryonic development likely has a role in the adult liver as well, Glimcher and her team began studying XBP1s function in liver using inducible knockouts.

Their first guess was that its role would be in regulating protein synthesis, similar to its known function in secretory cells. But "to our surprise, we found that the protein synthetic function of the adult liver was largely intact." Not only that, but "we didn't see any evidence of endoplasmic reticulum stress, either," she said.

Which led naturally to the next question: If there's no endoplasmic reticulum stress and proteins are normal, what else does the liver make? First author Ann-Hwee Lee decided to look at lipids, Glimcher said, "and that's when we saw that there was a profound absence of cholesterol and tricglycerides" in inducible liver-specific XBP1 knockouts.

Further studies confirmed that in the liver, XBP1 is induced by a high-carbohydrate diet and functions as a transcription factor that controls the synthesis of both triglycerides and cholesterol - though the details of how it does the latter have remained a mystery to date. While XBP1 activates at least three genes that are involved in triglyceride synthesis, "we still don't understand how it controls cholesterol," Glimcher said.

What is clear is that XBP1 does not cause fatty liver; the low plasma lipid levels that Glimcher and her team found were not accompanied by higher lipid levels in the liver, showing that liver fats are not synthesized in the first place, rather than synthesized and retained in the liver instead of making their way into the bloodstream.

Nor does XBP1 affect HMG-CoA reductase , the enzyme targeted by statins. This latter finding makes XBP1, Glimcher said, "another pathway to controlling dyslipidemias. So we're eager to find out" how it works - and whether it can be manipulated therapeutically. Glimcher's group is currently working, in collaboration with the Broad Institute, to identify small molecules or siRNAs that target XBP1.

Given the factor's well-known role in secretory cells, whether such targeting will ultimately be a viable clinical option is anyone's guess at this point. But Glimcher pointed out that like XBP1 knockouts, HMG-CoA reductase knockouts die before birth - "and statins are great drugs."

In the end, Glimcher said, whether targeting XBP1 is a viable therapeutic approach will depend on the details. "We know that you need XBP1 to generate antibodies. But transient inhibition, or even chronic inhibition at levels that affect lipids, may not affect antibodies," she said. And, she pointed out, less likely schemes have come to pass: "Who would have thought that you could inhibit the proteasome without massive toxicity?"