ATF4, Maybe Less Really Is More

ATF4 Protein Deficiency Protects against High Fructose-induced Hypertriglyceridemia in Mice

This article investigated the causes and effects of lipogenesis and it’s impact on the development of hypertriglyceridemia. Hypertriglyceridemia is the presence of abnormally high levels of triglycerides in your blood. This disease is commonly associated with obesity and type 2 diabetes. Hypertriglyceridemia is acquired when a person has either increased production and/or decreased clearance of triglyceride-rich lipoproteins. Due to the nature of the disease, this research group looked at the hepatic regulation of triglyceride metabolism, more specifically activating transcription factor 4 (ATF4).

The team identified the effects of ATF4 by comparing data collected from mice containing the gene and mice in which the gene was deficient (Atf4-/-). The mice were subjected to diets of varying in fructose content and studied were conducted over a long period of time analyzing the blood triglyceride concentration, fat mass with respect to gross weight and the percent of the mouse’ body weight, blood glucose levels, and overall caloric intake. The data collected showed that the Atf4-/- mice had a statistically significant decrease in the amount of triglycerides in the blood, fat mass, and overall body weight, despite intaking a statistically significant amount of calories more per mouse than the wild type mice.

The Journal of Biological Chemistry (2013), 288, 25350-25361
The Journal of Biological Chemistry (2013), 288, 25350-25361

After determining that an ATF4 deficiency can decrease fat content even with an increased intake of calories, the team turned their attention to how that was possible. They identified various previously-studied genes involved in hepatic lipogenesis and determined their relative concentrations in normal and Atf-/- mice. They found that some genes were upregulated, but that some were downregulated in Atf-/- mice. One of those genes happens to be sterol regulatory element-binding protein 1c (Srebp-1c) which is the “master regulator”  of lipogenesis. Furthermore, genes involved in fatty acid oxidation were shown to be unchanged between the two groups. Since a high-fructose diet is a lead contributor to obesity, the accumlation of excess fat, this discovery shows how ATF4 deficient individuals have a “protection” from the build up of excess fat because one of the components involved in lipogenesis is significantly reduced as a result of the deficiency. Since hypertriglyceridemia is a result caused by the increased production or decreased clearance of triglyceride-rich lipoproteins, the deficiency of ATF4 has been shown to decrease the rate of lipid production while maintaining the same rate of fatty acid oxidation.

One Reply to “ATF4, Maybe Less Really Is More”

  1. I found it interesting that the ATF4 gene when knocked down attenuates the fatty acid synthesis due to overaccumulation of fructose. Does identifying this gene as a point of regulation result in a therapeutic target in the future?

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