Tiny amounts of a specific type of lipid in the small intestine — unsaturated lysophosphatidic acids (LPAs) — may play a greater role than previously thought in generating the high cholesterol levels and inflammation that lead to clogged arteries. UCLA researchers also found they could reduce the negative effects of these lipids in mice by feeding the animals a new genetically engineered tomato being developed at UCLA that is designed to mimic HDL, so-called “good,” cholesterol.
Previously, it was thought that the role of the small intestine in response to a high-fat, high-cholesterol diet was simply to package the fat and cholesterol for transport to the liver, where it would cause increased blood levels of LDL (“bad”) cholesterol, decreased levels of “good” cholesterol and the rise of systemic inflammation. But the UCLA researchers revealed that LPAs, previously considered very minor because they are found in far smaller amounts in the small intestine than other lipids, may play a more direct role in contributing to the factors that cause atherosclerosis.
The research team, led by Alan Fogelman, MD ’66 (RES ’68, ’71, FEL ’73), executive chair of the Department of Medicine and director of the atherosclerosis research unit at the David Geffen School of Medicine at UCLA, found that mice fed a high-fat, high-cholesterol diet showed a twofold increase in the amount of LPAs in the small intestine over mice fed normal low-fat mouse chow. When researchers added LPAs at only one part per million to the normal low-fat, low-cholesterol mouse chow, they observed the same increase in LPAs in the small intestine as when the mice were fed the high-cholesterol, high-fat diet. Surprisingly, with the addition of LPAs to the low-fat diet, the UCLA team also found alterations in the patterns of gene expression in the small intestine, increases in LDL and decreases in HDL levels and increases in blood markers of inflammation typically seen when the mice consumed a high-fat, high-cholesterol diet.
The researchers then added 2.2 percent of freeze-dried tomato powder — made from a tomato engineered to produce a small peptide called 6F, which mimics the action of apoA-1, the chief protein of HDL — to low-fat, low-cholesterol mouse chow that was supplemented with LPAs. They also added the same dose of the peptideenhanced tomatoes to the high-fat high-cholesterol diet. In both cases, the addition prevented an increase in the level of LPAs in the small intestine and also stopped increases in “bad” cholesterol, decreases in “good” cholesterol and systemic inflammation.
“Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid,” Journal of Lipid Research, October 1, 2013