Pathophysiology

The protein coded by the DGAT1 gene is an enzyme that is involved in making triglycerides. Studying this enzyme in animal models led to the observation that mice without DGAT1 have decreased obesity, increased energy, are resistant to diet related obesity and fatty liver, are more sensitive to insulin, and live longer. Because of these observations, attempts were made to find medications that would inhibit DGAT1 in people, hoping that these favorable results would benefit people. However, inhibiting DGAT1 in humans did not produce the same desirable results as many of the subjects who participated in the clinical trials developed diarrhea.

There are a few theories about why lacking the ability to make triglycerides in the intestine might result in diarrhea nad loss of protein in the stool. One theory for what causes diarrhea is that the fats involved in triglyceride production accumulate in the cells that line the intestine resulting in defective absorption. In this theory, fat acts like a kind of toxin affecting the cells in the intestine that are responsible for absorbing nutrients and causing diarrhea. One interesting finding is the elevation of triglycerides in the blood of many children with DGAT1 deficiency. While this seems to be counterintuitive, it might be caused by an increase in triglyceride production in the liver mediated by another DGAT gene, DGAT2. Something similar may also be occuring in the intesting of mouse models of DGAT1 deficiency. The difference between humans and mice is that DGAT1 is primarily found in the human intestine; whereas, DGAT2 is found in the mouse intestine. Since DGAT2 is also present, this might explain why the mouse who is deficient in DGAT1 does not have diarrhea.

The location of the gene for DGAT1 is on the long arm (q) of chromosome 8 at position 24.3