April 2011

Getting the skinny on DGAT

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Diglyceride acyltransferase, known to lipidologists as DGAT, gets a lot of attention in the April issue of the Journal of Lipid Research, where it’s the focus of an article by researchers at Columbia University and AstraZeneca and a related commentary. What makes DGAT such a hot topic?  It’s an important enzyme in the formation of triglycerides, high levels of which have been linked to atherosclerosis, heart disease, and stroke. Inhibitors of DGAT have the potential to help fight obesity, and Phase 2 clinical trials currently are testing the efficacy of these agents in promoting weight loss and increasing insulin sensitivity.

Li Liu of Columbia University and colleagues studied mice with the DGAT1 gene knocked out to assess the impact of short- versus long-term loss of DGAT1 activity. The knockout mice were known to be resistant to obesity and insulin resistance, but it was unclear how the absence of DGAT1 led to these effects.

Lui and colleagues found that mice without DGAT1 had lower levels of messenger RNA for the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor proteins, which act as gatekeepers to regulate traffic between the nucleus and the cytoplasm. The mice also had lower mRNA levels of downstream target genes that are directly involved with lipid uptake and degradation. Expression of the glucose transporters GLUT1 and GLUT2 was found to be elevated as well. Thus, these findings show that loss of DGAT1 activity decreases mRNA levels of some genes involved in lipid uptake and oxidation.

Rinke Stienstra and Sander Kersten of Wageningen University in the Netherlands have written a commentary on Liu’s findings, suggesting that the next big questions in this area of study are how each of the different PPARs contributes to the resistance to obesity and increased insulin sensitivity observed in DGAT-deficient individuals or those who have impaired DGAT function, and what role the decreased activity of the PPARs has in preventing the cellular, tissue or organ damage usually caused by abnormally large amounts of lipids in the body. Another consideration they note is that the hearts of DGAT1-deficient mice have several characteristics similar to those of mice experiencing inflammatory processes like sepsis or infection with endotoxins, so it has been proposed that perhaps the lack of DGAT1 causes a similar inflammatory reaction. Further study is warranted to clarify the various ways DGAT1 affects the body as a whole so that one day this research can be applied to help the growing obesity epidemic.

Mary L. Chang (mchang@asbmb.org) is the managing editor of the Journal of Lipid Research.

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