Abstract
Imbalance of lipid metabolism is a main cause of metabolic syndrome leading to life-threatening metabolic diseases. Angiopoietin-like protein 8 (Angptl8) was recently identified as a liver and adipose tissue-released hormone that is one of the molecules involved in triglyceride metabolism. However, the regulatory mechanism of Angptl8 is largely unknown. A high fat diet (HFD)-fed mouse model, which showed high cholesterol, high triglyceride, and high insulin in the blood, revealed the upregulation of hepatic and plasma Angptl8 and the downregulation of hepatic glycine N-methyltransferase (GNMT). The inverse correlation of hepatic Angptl8 and GNMT expression in the livers of HFD-fed mice was also confirmed in a publicly available microarray dataset. The mechanistic study using primary hepatocytes showed that the Angptl8 expression could be induced by insulin treatment in a dose- and time-dependent manner. Inhibition of PI3K/Akt pathway by the specific inhibitors or the dominant-negative Akt blocked the insulin-induced Angptl8 expression. Moreover, knockout of GNMT promoted the Akt activation as well as the Angptl8 expression. These results suggested that GNMT might be involved in insulin-induced Angptl8 expression in HFD-mediated metabolic syndrome.
Highlights
Obesity and metabolic syndrome due to over-nutrition and sedentary lifestyle are the risk factors for nonalcoholic fatty liver disease, cardiovascular disease, and type 2 diabetes [1,2]
Our in vitro study using primary hepatocytes demonstrated that the insulin-activated PI3K/Akt signaling pathway significantly induced Angiopoietin-like protein 8 (Angptl8) expression in a dose and time-dependent manner
We found the treatment of insulin resulted in the phosphorylation of Akt, but did not alter the phosphorylation levels of ERK1/2 in the primary hepatocytes
Summary
Obesity and metabolic syndrome due to over-nutrition and sedentary lifestyle are the risk factors for nonalcoholic fatty liver disease, cardiovascular disease, and type 2 diabetes [1,2]. Angptl lacks the C-terminal fibrinogen-like domain [11] It has been identified as a hormone that is produced and released from liver and adipose tissues [12]. Losing weight by a calorie-restricted diet and activity decreases the plasma levels of Angptl8 [20,21] These findings from animal and clinical studies suggested that dysregulation of Angptl can be the cause and consequence of a metabolic syndrome. Since PTEN is an inhibitor of PI3K/Akt signaling cascade, depletion of GNMT results in the activation of Akt. Since GNMT and Angptl play an important role in lipid metabolism in physiological and pathological conditions, we hypothesized that GNMT may involve in Angptl expression. Our data suggested that the GNMT may function as a negative regulator for Angptl expression in metabolic syndrome
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