Abstract
Glycyrrhetinic acid (GA), a bioactive component in the human diet, has been reported to improve hyperglycemia, dyslipidemia, insulin resistance and obesity in rats with metabolic syndrome. However, GA-specific target proteins and the mechanisms involved in the downstream signaling and cross-talk to improve insulin sensitivity have not been fully elucidated. In this study, the potential targets of GA were identified by chemical proteomics strategies using serial GA probes for target fishing and cell molecular imaging. Intracellular enzyme activity evaluation and insulin resistance models were used for validating the function of the target proteins on the downstream insulin signaling pathways. Collectively, our data demonstrate that GA improved the insulin-responsive pathway and glucose consumption levels via multiple diabetogenic factors that activated the insulin signaling pathway in HepG2 cells. GA improved Glucose transporter 4(GLUT4) expression by targeting the Ras protein to regulate the mitogen-activated protein kinase (MAPK) pathway. GA exhibited a strong inhibitory effect on IRS1ser307 phosphorylation in cells treated with the Protein kinase C (PKC) activator Phorbol 12-myristate 13-acetate (PMA.) Consistently, IRS1ser307 phosphorylation was also inhibited by GA in Free fatty acid (FFA)-treated HepG2 cells. GA also inhibited the PMA-induced phosphorylation of IκB kinase α/β (IKKα/β), c-Jun N-terminal kinase (JNK) and p38 proteins (P38), suggesting that IKKα/β, JNK and P38 activation is dependent on PKC activity.
Highlights
Insulin resistance causes target tissues to fail to respond properly to normal levels of circulating insulin, which is a common pathological condition known as type 2 diabetes mellitus (T2DM).When insulin binds to its cognate receptor, it leads to the autophosphorylation and activation of the insulin receptor (IR)
Recent studies show that diabetogenic factors, such as free fatty acid (FFA) [3], TNF-α [4] and hyperinsulinemia, increase the serine phosphorylation of insulin receptor substrate (IRS)-1, and ser307/612/632 were identified as phosphorylated sites [2,5]
The results demonstrated that Glycyrrhetinic acid (GA) affected the action of Ras GTPases and Protein kinase C (PKC), regulated the cross-talk between the Ras/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, promoted glucose transporter type 4 (GLUT4) expression, reduced inflammation and improved insulin sensitivity
Summary
Insulin resistance causes target tissues to fail to respond properly to normal levels of circulating insulin, which is a common pathological condition known as type 2 diabetes mellitus (T2DM). When insulin binds to its cognate receptor (transmembrane tyrosine kinase receptor), it leads to the autophosphorylation and activation of the insulin receptor (IR). The activated IR phosphorylates several insulin receptor substrate (IRS) protein families. The IRS proteins (IRS-1 to IRS-4) play a crucial role in insulin signaling [1]. IRS-1 function is multifaceted and involves the phosphorylation of IRS-1 at multiple serine/threonine residues [2]. Recent studies show that diabetogenic factors, such as free fatty acid (FFA) [3], TNF-α [4] and hyperinsulinemia, increase the serine phosphorylation of IRS-1, and ser307/612/632 were identified as phosphorylated sites [2,5]
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