Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins

Abstract

Summary FoxO proteins are major targets of insulin action. Adipose triacylglycerol (TAG) lipase mediates the first step in TAG hydrolysis and FoxO1 stimulates ATGL expression in adipose tissue. Here, we report that FoxO1 also stimulates ATGL and suppresses expression of its inhibitor, the G0/G1 switch gene protein 2 (G0S2), in the liver. Studies in FoxO transgenic and knockout mice and hepatocytes show that FoxO proteins mediate effects of insulin on ATGL and G0S2 expression. Further, ATGL-dependent lipolysis mediates effects of FoxOs on glycolytic, lipogenic and gluconeogenic gene expression and metabolism, including fatty acid oxidation, which is required for effects of FoxO1 on glucose homeostasis. These results reveal that ATGL-dependent lipolysis and fatty acid oxidation play a critical role in integrating the regulation of glucose and lipid metabolism downstream from FoxO proteins in the liver, and suggest that targeting ATGL-dependent lipolysis and its downstream effectors may provide an effective strategy for improving the treatment of patients with diabetes and hepatic insulin resistance.

Unraveling the Regulation of Hepatic Metabolism by Insulin

“…Many of the studies of FoxO transcription factors have focused on the predominant FoxO transcription factor in liver, FoxO1. Transgenic mice that express in liver a mutated version of FoxO1 (FoxoAAA) that cannot be phosphorylated by Akt and therefore is constitutively active [31, 32], display reduced de novo lipogenesis, and triglyceride secretion, and fail to induce of the lipogenic gene program in response to a meal [33–35]. Consistent with this, hepatic deletion of all three FoxO transcription factors induce de novo lipogenesis, hepatic steatosis, and increases in lipogenic gene expression [36].…”

G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux

“…Thus, it would be tempting to determine whether G0S2 is also under the dual regulation of LXRα and PPARα. Furthermore, Zhang et al have recently shown that FoxO1 promotes intrahepatic lipolysis and FA oxidation through concomitantly stimulating ATGL and suppressing G0S2 expression [103]. Interestingly, FoxO1 is known to antagonize de novo lipogenesis via reducing the binding of LXRα to the SREBP-1c promoter [104, 105].…”

FOXO transcription factors in non-alcoholic fatty liver disease

“…20,21,23,29,31,36–38 Moreover, FOXOs activate lipolysis and fatty acid oxidation genes including adipose triacylglycerol lipase, hormone-sensitive lipase, lipoprotein lipase, and carnitine palmitoyltransferase 1. 21,31,37,38,42 Interestingly, FOXO1 also suppresses expression of the G0/G1 switch-2 gene that encodes an inhibitor of adipose triacylglycerol lipase. 37 FOXO1 has been shown to upregulate fatty acid transporters such as Leukocyte differentiation antigen CD36.…”

“…21,31,37,38,42 Interestingly, FOXO1 also suppresses expression of the G0/G1 switch-2 gene that encodes an inhibitor of adipose triacylglycerol lipase. 37 FOXO1 has been shown to upregulate fatty acid transporters such as Leukocyte differentiation antigen CD36. 43 In addition, FOXOs promote lipid droplet breakdown through activation of lipophagy, an autophagy process that degrades lipid droplets for energy production.…”

“…29,31,36 Overexpression of a constitutively active FOXO1 transgene reduces hepatic triglyceride content. 37,38 When challenged by high-fat diets, FoxO1/3/4 liver-specific knockout mice develop very severe hepatic steatosis, especially on a high-fat plus cholesterol diet. 29 …”