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

• DOI: 10.1074/jbc.m113.470526
• Publication Date: 2013-07-26T11:49:23Z
• Authors: Guozhi Xiao; Ting Zhang; Shibing Yu; Sojin Lee; Virtu Calabuig-Na...; Jun Yamauchi; Steven Ringquist; H. Henry Dong
• Keywords: Hypertriglyceridemia; Mice, Knockout; 2. Zero hunger; 0303 health sciences; Fructose; Lipid Metabolism; Activating Transcription Factor 4; Fatty Acid Synthase, Type I; PPAR gamma; Mice; 03 medical and health sciences; Liver; Sweetening Agents; Animals; Sterol Regulatory Element Binding Protein 1; Acetyl-CoA Carboxylase

Hypertriglyceridemia is the most common lipid disorder in obesity and type 2 diabetes. It results from increased production and/or decreased clearance of triglyceride-rich lipoproteins. To better understand the pathophysiology of hypertriglyceridemia, we studied hepatic regulation of triglyceride metabolism by the activating transcription factor 4 (ATF4), a member of the basic leucine zipper-containing protein subfamily. We determined the effect of ATF4 on hepatic lipid metabolism in Atf4(-/-) mice fed regular chow or provided with free access to fructose drinking water. ATF4 depletion preferentially attenuated hepatic lipogenesis without affecting hepatic triglyceride production and fatty acid oxidation. This effect prevented excessive fat accumulation in the liver of Atf4(-/-) mice, when compared with wild-type littermates. To gain insight into the underlying mechanism, we showed that ATF4 depletion resulted in a significant reduction in hepatic expression of peroxisome proliferator-activated receptor-γ, a nuclear receptor that acts to promote lipogenesis in the liver. This effect was accompanied by a significant reduction in hepatic expression of sterol regulatory element-binding protein 1c (SREBP-1c), acetyl-CoA carboxylase, and fatty-acid synthase, three key functions in the lipogenic pathway in Atf4(-/-) mice. Of particular significance, we found that Atf4(-/-) mice, as opposed to wild-type littermates, were protected against the development of steatosis and hypertriglyceridemia in response to high fructose feeding. These data demonstrate that ATF4 plays a critical role in regulating hepatic lipid metabolism in response to nutritional cues.