Sci. Aging Knowl. Environ., 18 January 2006
Vol. 2006, Issue 3, p. nf3
[DOI: 10.1126/sageke.2006.3.nf3]


Double Duty

Cholesterol-reducing receptor also curbs blood glucose

Mitch Leslie

Succeeding at two different jobs is tough. Take basketball superstar Michael Jordan's failed attempt to play baseball or actor Leonard Nimoy's abortive singing career. But according to new research, a metabolic protein adroitly pulls off two disparate tasks: controlling cholesterol concentrations as well as glucose amounts in the blood. The work shows that the protein helps diabetic mice rein in lipids and sugar. The discovery might lead to treatments that allow people with diabetes to do the same.

Blood-glucose quantities soar in people with type II diabetes because body cells develop insulin resistance; they stop responding to the hormone, which normally spurs sugar absorption. The disease hits patients with a double whammy. Excess blood sugar damages tissues, and blood fats jump, boosting the risk of strokes and heart attacks. One potential fat fighter that has grabbed scientists' attention is the farnesoid X receptor (FXR). This protein toils in the cell nucleus and helps manage cholesterol and triglycerides, another type of lipid linked to cardiovascular disease. Previous research on cultured cells hinted that FXR also helped govern blood glucose amounts, but the studies differed over whether FXR increased or decreased them. To clarify FXR's role, biochemist Peter Edwards of the University of California, Los Angeles, and colleagues tested its effects on sugar metabolism in mice.

The researchers had noticed that dosing mouse liver cells with an FXR activator altered the activity of genes involved in glucose production. They followed up those observations by feeding the activator to diabetic mice. The compound slashed the amounts of glucose, cholesterol, and triglycerides in the blood. It had a similar but smaller effect on normal mice. Rodents that lacked the FXR gene showed no improvement. One way for the body to reduce blood glucose is to transform the molecule into glycogen, a reaction that occurs in the liver. The activator boosted glycogen production in the livers of diabetic mice, the team found. It also turned down the output of two genes whose products help make glucose. When the researchers used a genetically engineered virus to spur only the rodents' livers to pump out extra FXR, they discovered that glucose quantities declined. That finding suggests that cranking up FXR activity in the liver is sufficient to pull down blood glucose amounts. Overall, the work indicates that FXR plays a surprising dual role, reigning over lipids and glucose, says Edwards. He adds that to his knowledge, no FXR-prodding drugs are ready for clinical trials. But if researchers can craft such compounds, they might forestall two causes of damage in diabetes.

The paper dispels the uncertainty about FXR's effects on blood sugar, says molecular biologist David Moore of Baylor College of Medicine in Houston, Texas. The receptor "has a positive impact on glucose metabolism," he says, because it cuts the amount of circulating glucose. However, he notes that the liver isn't the only organ that malfunctions in diabetes. For example, the muscles develop insulin resistance. Future work should determine whether spurring FXR adjusts insulin sensitivity in other parts of the body, he says. Those studies might give us further reason to admire FXR's versatility.

January 18, 2006
  1. Y. Zhang et al., Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl. Acad. Sci. U.S.A., 12 January 2006 [e-pub ahead of print]. doi:10.1073/pnas.0506982103 [Abstract/Free Full Text]
Citation: M. Leslie, Double Duty. Sci. Aging Knowl. Environ. 2006 (3), nf3 (2006).

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