Throwing doubt on how niacin works

August 23, 2012 § Leave a comment

Ball-and-stick representation of niacin. Image from http://en.wikipedia.org/wiki/File:Niacin-3D-balls.png

Just when you think you have a molecule figured out, along come data that turn your confidence into doubt. In a paper in this week’s Science Translational Medicine, researchers suggest that the vitamin niacin does not work the way experts have believed for decades.

Niacin is used to treat atherosclerosis and a condition called dyslipidemia where patients have abnormal cholesterol levels. Researchers have thought that the vitamin changes cholesterol levels through its effects on free fatty acids. This mode of action is known as the free fatty acid hypothesis.

But a study led by Brett Lauring and Andrew Plump at Merck has thrown doubts on the hypothesis. The investigators looked at a receptor called GPR109A in mice and examined data collected from humans.

Niacin was thought to reduce the breakdown of triglyceride in fat cells called adipocytes. It was thought to bind GPR109A at the cell surface of adipocytes and set off signaling pathways to slow down triglyceride breakdown into glycerol and free fatty acids. The reduction in triglyceride breakdown led to a drop in the amount of free fatty acid in the blood.

The drop in blood free fatty acid was thought to then cause less free fatty acid uptake by the liver. The liver is in charge of making low-density lipoproteins.  If the liver were to take up less free fatty acid, the thinking went, it would make less LDL (informally called bad cholesterol). Less LDL in the blood ultimately would cause an increase in the amount of high-density lipoproteins (informally called good cholesterol).

But the data in this latest paper suggest something else is going on. The investigators said that other activators of GPR109a had similar effects on free fatty acids but didn’t change the LDL, HDL or triglyceride levels. The data refuted the big free fatty acid hypothesis.

The old suggestion that GPR109a was the niacin receptor had “set us and others up to rationally design the perfect niacin medicine,” Plump and Lauring said in a statement. But now, it turns out that the most promising target of niacin, GPR109a, is not responsible for niacin’s lipid efficacy.  The free fatty hypothesis doesn’t explain how niacin lowers cholesterol levels.

Plump and Lauring noted that this disappointment points to the challenges of drug discovery. “Even when it looks like everything lines up perfectly, one needs to be highly critical and perform the right experiments,” they said.  “We also need to continue to evolve a mechanism for optimally and efficiently translating basic academic discoveries to medical therapies.”

So if niacin doesn’t need GPR109a for its mode of action,  how does it work? That, Plump and Lauring said, is now  the million-dollar question.

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