Abstract
Mangiferin has been shown to have the effect of improving dyslipidemia. Plasma free fatty acids (FFA) are closely associated with blood lipid metabolism as well as many diseases including metabolic syndrome. This study is to investigate whether mangiferin has effects on FFA metabolism in hyperlipidemic rats. Wistar rats were fed a high-fat diet and administered mangiferin simultaneously for 6 weeks. Mangiferin (50, 100, 150 mg/kg BW) decreased dose-dependently FFA and triglycerides (TG) levels in plasma, and their accumulations in liver, but increased the β-hydroxybutyrate levels in both plasma and liver of hyperlipidemic rats. HepG2 cells were treated with oleic acid (OA, 0.2 mmol/L) to simulate the condition of high level of plasma FFA in vitro, and were treated with different concentrations of mangiferin simultaneously for 24 h. We found that mangiferin significantly increased FFA uptake, significantly decreased intracellular FFA and TG accumulations in HepG2 cells. Mangiferin significantly increased AMP-activated protein kinase (AMPK) phosphorylation and its downstream proteins involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1), but significantly decreased acyl-CoA: diacylgycerol acyltransferase 2 (DGAT2) expression and acetyl-CoA carboxylase (ACC) activity by increasing its phosphorylation level in both in vivo and in vitro studies. Furthermore, these effects were reversed by Compound C, an AMPK inhibitor in HepG2 cells. For upstream of AMPK, mangiferin increased AMP/ATP ratio, but had no effect on LKB1 phosphorylation. In conclusion, mangiferin decreased plasma FFA levels through promoting FFA uptake and oxidation, inhibiting FFA and TG accumulations by regulating the key enzymes expression in liver through AMPK pathway. Therefore, mangiferin is a possible beneficial natural compound for metabolic syndrome by improving FFA metabolism.
Highlights
A large body of evidence suggests that elevated plasma free fatty acids (FFA) are a risk factor for metabolic syndrome, including insulin resistance, atherogenic dyslipidemia and type 2 diabetes [1,2]
Mangferin had no toxic effect in rats and HepG2 cells Rats were fed with different concentrations of mangiferin (0, 100, 200, 400 mg/kg BW) for 30 days
The effects of mangiferin on oleic acid (OA) uptake, intracellular OA and TG (Figure 4A) contents, as well as the expression of AMPK downstream proteins, including CD36, carnitine palmitoyltransferase 1 (CPT1), P-acetyl-CoA carboxylase (ACC) and diacylgycerol acyltransferase 2 (DGAT2) were suppressed significantly after compound C treatment (P,0.05, Figure 4B). These results strongly suggest that mangiferin exerts its effect on lowering plasma FFA level, promoting FFA uptake and oxidation, inhibiting FFA and TG synthesis via the AMPK signaling pathway in liver
Summary
A large body of evidence suggests that elevated plasma free fatty acids (FFA) are a risk factor for metabolic syndrome, including insulin resistance, atherogenic dyslipidemia and type 2 diabetes [1,2]. Pharmacological agents that could effectively lower plasma FFA are likely to have a significant effect on improving metabolic syndrome [5]. Not surprisingly, increased plasma FFA levels may result in intracellular accumulation of lipid metabolites in the liver, leading to fatty liver, liver insulin resistance and type 2 diabetes. One potential strategy for improving metabolic syndrome is to reduce the level of plasma FFA, and to promote FFA uptake and oxidation instead of accumulation of intracellular TG in the liver
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