A Novel Function of Hepatic FOG2 in Insulin Sensitivity and Lipid Metabolism Through PPARα

Abstract

Friend of GATA 2 (FOG2) is a transcriptional cofactor involved mostly in cardiac function. The aim of this study was to investigate the role of hepatic FOG2 in insulin sensitivity and lipid accumulation. FOG2 overexpression by adenovirus-expressing FOG2 (Ad-FOG2) significantly attenuates insulin signaling in hepatocytes in vitro. Opposite effects were observed when FOG2 was knocked down through adenovirus-expressing small hairpin RNA for FOG2 (Ad-shFOG2). Furthermore, FOG2 knockdown by Ad-shFOG2 ameliorated insulin resistance in leptin receptor-mutated (db/db) mice, and FOG2 overexpression by Ad-FOG2 attenuated insulin sensitivity in C57BL/6J wild-type (WT) mice. In addition, Ad-FOG2 reduced, whereas Ad-shFOG2 promoted, hepatic triglyceride (TG) accumulation in WT mice under fed or fasted conditions, which was associated with increased or decreased hepatic peroxisome proliferator-activated receptor a (PPARa) expression, respectively. Moreover, the improved insulin sensitivity and increased hepatic TG accumulation by Ad-shFOG2 were largely reversed by adenovirusexpressing PPARa (Ad-PPARa) in WT mice. Finally, we generated FOG2 liver-specific knockout mice and found that they exhibit enhanced insulin sensitivity and elevated hepatic TG accumulation, which were also reversed by AdPPARa. Taken together, the results demonstrate a novel function of hepatic FOG2 in insulin sensitivity and lipid metabolism through PPARa.Insulin resistance is a risk factor for type 2 diabetes (T2D), and dysregulated hepatic lipid metabolism is the major cause of nonalcoholic fatty liver disease. Many studies have demonstrated a relationship between T2D and nonalcoholic fatty liver disease. For example, insulin resistance has been shown to accompany liver steatosis (1-3). On the other hand, improved insulin sensitivity sometimes is not enough to ameliorate disrupted lipid metabolism (4-6). These results suggest a complex relationship between the regulation of insulin sensitivity and hepatic lipid metabolism. Because the liver is critical in the regulation of glucose and lipid metabolism, the function of many genes expressed in the liver needs to be explored.Friend of GATA 2 (FOG2, also known as ZFPM2) was first cloned from mouse embryonic brain (7) and heart (8). FOG2 is expressed in many tissues (8,9) and functions as a coregulator of the transcriptional factor GATA family (7,8). Studies have shown that FOG2 is involved in the regulation of many physiological processes, including coronary vascular development and heart morphology (10-12). However, some studies have implied a possible role of FOG2 in the regulation of insulin signaling and lipid metabolism such that FOG2 can bind to the regulatory unit p85 of phosphatidylinositol 3-kinase (PI3K) and attenuate phosphorylation of protein kinase B (AKT), the major component of insulin signaling in various cell types (13). Furthermore, FOG2 expression is increased in liver of insulin-resistant mice induced by interleukin-6 injection or with mutation in leptin receptor (db/db) (14). Moreover, ...

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