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Eaten cholesterol barely enters the body
What cholesterol does
Cholesterol is made by every cell and makes up the cell membrane of every cell, keeping it fluid. It is also the backbone of estrogen, progesterone, testosterone, and cortisol, and it forms the bile salts needed to digest food. Genetic conditions that impair its synthesis can be fatal in utero.
The gut's gatekeepers
The cells lining the gut carry two transporters. The Niemann-Pick C1-like 1 transporter admits any sterol that fits through the door, almost all of it the body's own cholesterol returning in bile, and it is the checkpoint where the body decides whether it has enough. The ATP-binding cassette G5/G8 transporter pushes the excess back into the gut to be excreted.
Why food cholesterol stays out
Cholesterol in food is esterified, with a big, bulky side chain attached, and it physically can't pass through that first transporter. Perhaps 10% to 15% gets de-esterified and enters, a small fraction of the body's cholesterol pool. Dietary cholesterol plays no role in serum cholesterol, which Ancel Keys acknowledged in the 1960s and the American Heart Association accepted decades later.
Saturated fat is a different molecule: a long fatty acid with no double bonds. The observation that eating saturated fat raises cholesterol is generally correct.
How did guidelines change on dietary cholesterol?
For decades, US dietary guidelines capped cholesterol intake at 300 milligrams a day. The American Heart Association and American College of Cardiology removed the cap in their 2013 lifestyle guidelines, citing insufficient evidence. The 2015 Dietary Guidelines Advisory Committee report concluded that cholesterol was not a nutrient of concern for overconsumption, and the 2015 to 2020 Dietary Guidelines for Americans dropped the numeric limit.
How was the gut cholesterol transporter found?
Scientists at Schering-Plough identified NPC1L1 as the target of the drug ezetimibe in a 2004 paper in Science led by Scott Altmann. The drug had been approved in 2002, so it was in use for two years before its target was known. Mice lacking NPC1L1 absorbed far less cholesterol, and ezetimibe had no further effect in them.
Why does the gut push some sterols back out?
The ABCG5 and ABCG8 transporters pair up to pump plant sterols and excess cholesterol back into the gut. Mutations in either gene cause sitosterolemia, a rare inherited disease in which plant sterols accumulate in the blood and tissues. Researchers in Helen Hobbs's laboratory at UT Southwestern traced the condition to these genes in 2000 and 2001.
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