Although the transcription factor XBP1 is best known for its role in the stress response of the endoplasmic reticulum (ER), principal investigator Laurie Glimcher, the Irene Heinz Given professor of immunology at HSPH, and colleagues have found a key role for the molecule in hepatic lipogenesis. They show in the June 13 Science that conditionally deleting XBP1 in the adult liver decreases cholesterol, triglycerides, and free fatty acids in the blood without any accompanying fat accumulation in liver cells. The findings make XBP1 a promising therapeutic target against human dyslipidemias, such as high cholesterol, which can lead to atherosclerosis.
“We discovered the factor 20 years ago when we were working on a totally different area,” said Glimcher, who is also an HMS professor of medicine at Brigham and Women’s Hospital. The first attempt to uncover its function, in which Glimcher deleted XBP1 from the whole animal, resulted in death in utero. After eventually circumventing this embryonic lethality, Glimcher and colleagues discovered in 2003 that XBP1 was required for plasma cell differentiation. This would turn out to be just one of the many functions of XBP1.
“About six months after we published that paper,” Glimcher recalled, “three groups … independently discovered that XBP1 was the long-sought mammalian homolog of the yeast factor hac1p, so that led us into the ER stress response field.” Also known as the unfolded protein response, the stress response is activated during times of cellular stress to repair or refold misfolded proteins in the ER.
Research from the Glimcher lab and others developed the idea that “XBP1 increases the folding capacity of the cells by both increasing the ER membrane as well as by increasing the ER chaperone proteins,” said Ann-Hwee Lee, research scientist in the Glimcher lab and first author on the recent paper. “But this was all in vitro…. Our goal was to know what is the function [of XBP1] in vivo.”
So Lee created a mouse in which he specifically deleted XBP1 in the adult liver. To the group’s surprise, this elimination hardly affected levels of plasma protein produced by the liver, including proteins that would normally be altered by the ER stress response. Because work from other groups had shown that XBP1 regulates phospholipid biosynthesis in yeast, they decided to expand their investigation.
To broadly examine changes that hepatic XBP1 deletion might have on lipid levels, they performed a serum profile analysis on mice with the deletion, similar to the kind of tests normally run on human patients. The results were stunning. The levels of serum triglycerides, free fatty acids, and cholesterol dropped significantly in animals lacking XBP1 in the liver. This finding showed for the first time that XBP1 had a major regulatory role in the formation of lipids other than ER membrane phospholipids. The pathway did not seem to be associated with the ER stress response, providing a completely novel role for XBP1.
How does hepatic XBP1 change lipid levels? “Most of the lipid in the blood comes from the liver. Dietary lipid—the fat that you eat—is absorbed into the intestine, then it goes to the liver and then is repackaged in lipoprotein particles and secreted to the bloodstream,” Lee explained.
The decreased serum lipid levels that Glimcher’s group saw in the hepatic XBP1-deficient mice could occur in one of two ways. The liver could either be making fewer lipids or it could be generating the same overall level of lipids but secreting fewer of them. If it were the latter option, fats would build up in the liver, leading to hepatic steatosis, or fatty liver, which can accompany metabolic disorder. In collaboration with David Cohen, HMS associate professor of medicine and director of hepatology at Brigham and Women’s Hospital, and Cohen’s postdoctoral fellow Erez Scapa, the researchers discovered a huge decrease in lipid synthesis in XBP1-lacking cells. This finding, combined with the lack of hepatic steatosis, led the researchers to conclude that the lower lipid level seen in XBP1-deficient mice resulted from decreased synthesis of new lipids rather than any change in lipid secretion.
Blocking the lipid biosynthesis pathway is an efficient treatment for dyslipidemia, as demonstrated by statins, the most popular cholesterol medications, which decrease cholesterol biosynthesis. Given that XBP1 controls both sterol and fatty acid biosynthesis, a compound that targets this pathway may simultaneously control both hypercholesterolemia and hypertriglyceridemia. Harvard has recognized this possibility by awarding Glimcher’s lab a competitive grant from the Harvard Accelerator Fund, allowing them to begin work on high-throughput screenings to identify small molecule inhibitors of XBP1.
Glimcher’s group could activate the XBP1 lipogenesis pathway by feeding mice a high-carbohydrate diet or by adding high levels of glucose to cultured hepatocytes, implicating XBP1 in the pathway converting sugars to fats. Glimcher and colleagues will perform additional studies to figure out how the abundance of ingested carbohydrate activates the XBP1 lipogenesis pathway, but they are following other exciting new lines of research as well. They are looking ahead to experiments examining roles of XBP1 in other cell types and organs, as well as in models of human diseases such as metabolic syndrome, insulin resistance, atherosclerosis, and non-alcoholic hepatic steatosis.
“We think there may be a whole different understanding emerging … of what this signaling pathway does in different organs that is really separate from the ER stress response,” said Glimcher. “It’s going to be an interesting next year or two as we start to sort this out.”
