Loss of Glycine N-Methyltransferase Associates with Angiopoietin-Like Protein 8 Expression in High Fat-Diet-Fed Mice

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.

Disrupted liver oxidative metabolism in glycine N-methyltransferase-deficient mice is mitigated by dietary methionine restriction

“…Studies in humans [ 15 , 17 , [21] , [22] , [23] , [24] , [25] , [26] ] and experimental models [ [15] , [16] , [17] , [18] , [19] , [20] ] have identified that decreased GNMT expression is common in NAFLD and NAFLD-associated HCC. A causal role for the loss of GNMT in NAFLD pathophysiology is supported by findings that GNMT-null mice develop liver steatosis that progresses to HCC [ 28 , 29 , [32] , [33] , [34] ].…”

“…Mouse models of NAFLD-associated HCC routinely show decreased expression of one-carbon metabolism enzymes such as glycine N-methyltransferase (GNMT) [ [15] , [16] , [17] , [18] , [19] , [20] ]. Moreover, GNMT expression is lower or absent in human NAFLD and HCC [ 15 , 17 , [21] , [22] , [23] , [24] , [25] , [26] ].…”

Time-restricted feeding promotes skeletal muscle function in diet- and genetic-induced obesity through shared and unique pathways

“…Additionally, a related study observed that SAM was increased in overfed humans 8,52 further supporting the findings. Another recent study also revealed that upon a high fat diet challenge in mice, GNMT was downregulated 53 . There is currently little known regarding the role of GNMT in skeletal muscle, however both mRNA and protein levels have been observed in the skeletal soleus in mice 54 .…”