Abstract
One of the key events during the development of alcoholic liver disease (ALD) is that alcohol inhibits the insulin signaling pathway in liver and leads to disorders of glucose and lipid metabolism. Methyl ferulic acid (MFA) is a biologically active monomer isolated from the root of Securidaca inappendiculata Hasskarl. It has been reported that MFA has a hepatoprotective effect against alcohol-induced liver injury in vivo and in vitro. However, the effect of MFA on ethanol-induced insulin resistance in ALD remains unclear. In this study, we investigated whether MFA could exert protective effects against hepatic insulin resistance in ethanol-induced L-02 cells and ALD rats. ALD was induced in vivo by feeding Lieber-DeCarli diet containing 5% (w/v) alcohol for 16 weeks to Sprague-Dawley rats. Insulin resistance was induced in vitro in human hepatocyte L-02 cells with 200 mM ethanol for 24 h followed by 10-7 nM insulin for 30 min. MFA exhibited the effects of inhibited insulin resistance, reduced enzymatic capacity for hepatic gluconeogenesis, and increased hepatic glycogen synthesis both in vivo and in vitro. In addition, the results of transcriptome sequencing of liver tissues in the ethanol- and MFA-treated groups indicated that “pyruvate metabolism,” “glycolysis/gluconeogenesis,” and “fatty acid metabolism” were significantly different between ethanol- and MFA-treated groups. Further studies suggested that MFA activated the hepatic phosphatidylinositol 3-kinase (PI3K)/AKT pathway in vivo and in vitro. Taken together, these findings suggested that MFA effectively ameliorated hepatic insulin resistance in ALD at least partially by acting on the PI3K/AKT pathway.
Highlights
Recent epidemiological studies have shown that ethanol abuse has become one of the major determinants of chronic noncommunicable diseases such as alcoholic liver disease (ALD), cardiovascular disease, and type 2 diabetes mellitus (T2DM) (Parry et al, 2011)
The main findings of this study were as follows: 1) Methyl ferulic acid (MFA) reduced the enzymatic capacity for gluconeogenesis and increased glycogen synthesis in alcohol-induced rats, 2) MFA reduced the enzymatic capacity for gluconeogenesis and increased glycogen synthesis in ethanol-induced L-02 cells, and 3) our in vivo and in vitro studies showed for the first time that MFA attenuated ethanol-induced hepatic insulin resistance at least partially by enhancing the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway
We developed an in vivo model of ALD by feeding SD rats liquid Lieber-DeCarli diet for 16 weeks to study chronic ethanolinduced hepatic insulin resistance
Summary
Recent epidemiological studies have shown that ethanol abuse has become one of the major determinants of chronic noncommunicable diseases such as alcoholic liver disease (ALD), cardiovascular disease, and type 2 diabetes mellitus (T2DM) (Parry et al, 2011). In the liver, activated AKT has four main roles (Carr and Correnti, 2015): 1) stimulation of glycogen production by inhibiting glycogen synthase (GS) kinase (GSK) to increase GS activity (Beurel et al, 2015); 2) suppression of gluconeogenesis in part by inactivating forkhead box O1 (FoxO1) to decrease the expression of key gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (PEPCK), glucose-6phosphatase (G-6-Pase), and fructose 1,6-bi-phosphatase (FBPase) (Gross et al, 2009; Naowaboot et al, 2016; Ghanem et al, 2017); 3) stimulation of endogenous fatty acid synthesis by regulating sterol regulatory element-binding protein 1 (SREBP1) (Shao and Espenshade, 2012); and 4) promoting glucose transporter 2 (GLUT2) to transport glucose from the periphery into the cells for aerobic metabolism or anaerobic degradation (Xuguang et al, 2019). We established ethanol-induced rat and cell models of insulin resistance to investigate whether MFA had a therapeutic effect on insulin resistance and explored its effects on hepatic gluconeogenesis and glycogen synthesis
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