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Cited by 117Mangiferin and Mango ExtractsNatural Antidiabetic Agents StudiesMetabolism, Diabetes, and Cancer

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Mangiferin Decreases Plasma Free Fatty Acids through Promoting Its Catabolism in Liver by Activation of AMPK

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Niu, Yucun, Li, Songtao, Na, Lixin, Feng, Rennan, Liu, Liyan, Li, Ying, Sun, Changhao·2012·PLoS ONE
DOI 10.1371/journal.pone.0030782PMC PMC3264633
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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.

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Figure 1 Effects of mangiferin on the proteins expression of FFA metabolism including AMPK, CD36, CPT1, ACC and DGAT2 in liver of hyperlipidemic rats. Wistar rats were divided randomly into five groups (n = 10 per group): control group (fed an AIN-93G diet); hyperlipidemia group (fed a high-fat diet); mangiferin-supplemented groups, fed the high-fat diet and different doses of mangiferin (50, 100, 150 mg/kg BW/d). The experiment lasted for 6 weeks, and the liver was taken for western blot analysis. (A) AMPK phosphorylation level. (B) CD36 expression on cell membrane. (C) CPT1 expression in mitochondrion. (D) ACC level and activity. (E) DGAT2 expression. * P<0.05 compared with hyperlipidemic group.
Figure 1 Effects of mangiferin on the proteins expression of FFA metabolism including AMPK, CD36, CPT1, ACC and DGAT2 in liver of hyperlipidemic rats. Wistar rats were divided randomly into five groups (n = 10 per group): control group (fed an AIN-93G diet); hyperlipidemia group (fed a high-fat diet); mangiferin-supplemented groups, fed the high-fat diet and different doses of mangiferin (50, 100, 150 mg/kg BW/d). The experiment lasted for 6 weeks, and the liver was taken for western blot analysis. (A) AMPK phosphorylation level. (B) CD36 expression on cell membrane. (C) CPT1 expression in mitochondrion. (D) ACC level and activity. (E) DGAT2 expression. * P<0.05 compared with hyperlipidemic group.CC BY · PubMed Central
Figure 2 Effects of mangiferin on OA in medium, intracellular OA and intracellular TG in HepG2 cells. HepG2 cells were incubated with 0.2 mmol/L OA only or with different concentrations of mangiferin (12.5, 25, 50, 100 µmol/L) or fenofibrate (100 µmol/L) simultaneously for 24 h. The concentrations of OA in medium (A) and intracellular OA (B) after the incubation were determined by GC-MS. The intracellular TG (C) mass was quantified by the enzymatic methods using a TG test kit. Data are presented as means ± SD (n = 3). # P<0.05 and ## P<0.01 compared with the normal control. * P<0.05 and ** P<0.01 compared with only OA stimulation group.
Figure 2 Effects of mangiferin on OA in medium, intracellular OA and intracellular TG in HepG2 cells. HepG2 cells were incubated with 0.2 mmol/L OA only or with different concentrations of mangiferin (12.5, 25, 50, 100 µmol/L) or fenofibrate (100 µmol/L) simultaneously for 24 h. The concentrations of OA in medium (A) and intracellular OA (B) after the incubation were determined by GC-MS. The intracellular TG (C) mass was quantified by the enzymatic methods using a TG test kit. Data are presented as means ± SD (n = 3). # P<0.05 and ## P<0.01 compared with the normal control. * P<0.05 and ** P<0.01 compared with only OA stimulation group.CC BY · PubMed Central
Figure 3 HepG2 cells were incubated with 0.2 mmol/L OA only or with different concentrations of mangiferin (12.5, 25, 50, 100 µmol/L) simultaneously for 24 h. Proteins were isolated from the cell lysates and analyzed by western blot analysis for AMPK (A), CD36 (B), CPT1 (C), ACC (D) and DGAT (E) expressions. The experiments were repeated 3 times. Data are presented as means ± SD (n = 3). * P<0.05 compared with only OA stimulation group.
Figure 3 HepG2 cells were incubated with 0.2 mmol/L OA only or with different concentrations of mangiferin (12.5, 25, 50, 100 µmol/L) simultaneously for 24 h. Proteins were isolated from the cell lysates and analyzed by western blot analysis for AMPK (A), CD36 (B), CPT1 (C), ACC (D) and DGAT (E) expressions. The experiments were repeated 3 times. Data are presented as means ± SD (n = 3). * P<0.05 compared with only OA stimulation group.CC BY · PubMed Central
Figure 4 Effects of compound C on mangiferin induced FFA uptake, intracellular FFA, TG and FFA metabolism proteins expression in HepG2 cells. HepG2 cells were pretreated 1 h with compound C, an AMPK inhibitor, and then treated with 100 µmol/L mangiferin and 0.2 mmol/L OA for 24 h. OA in medium (To assess the uptake of OA) (A), intracellular OA (A), intracellular TG (A) and proteins expression of FFA metabolism including AMPK (B), ACC (B), CD36 (B), CPT1 (B) and DGAT2 (B) were determined by western blot method. The experiments were repeated 3 times. Data are presented as means ± SD (n = 3). * P<0.05 and ** P<0.01 compared with only OA stimulation group.
Figure 4 Effects of compound C on mangiferin induced FFA uptake, intracellular FFA, TG and FFA metabolism proteins expression in HepG2 cells. HepG2 cells were pretreated 1 h with compound C, an AMPK inhibitor, and then treated with 100 µmol/L mangiferin and 0.2 mmol/L OA for 24 h. OA in medium (To assess the uptake of OA) (A), intracellular OA (A), intracellular TG (A) and proteins expression of FFA metabolism including AMPK (B), ACC (B), CD36 (B), CPT1 (B) and DGAT2 (B) were determined by western blot method. The experiments were repeated 3 times. Data are presented as means ± SD (n = 3). * P<0.05 and ** P<0.01 compared with only OA stimulation group.CC BY · PubMed Central
Figure 5 Effects of mangiferin on the ratio of AMP to ATP and LKB1 protein expression in HepG2 cells. HepG2 cells were incubated to 0.2 mmol/L oleic acid only or with different concentrations of mangiferin (12.5, 25, 50, 100 µmol/L) simultaneously for 24 h. The ratio of AMP to ATP was detected by HPLC (A). The LKB1 protein expression was carried out by western blot analysis (B). The experiments were repeated 3 times. Data are presented as means ± SD (n = 3). * P<0.05 compared with only OA stimulation group.
Figure 5 Effects of mangiferin on the ratio of AMP to ATP and LKB1 protein expression in HepG2 cells. HepG2 cells were incubated to 0.2 mmol/L oleic acid only or with different concentrations of mangiferin (12.5, 25, 50, 100 µmol/L) simultaneously for 24 h. The ratio of AMP to ATP was detected by HPLC (A). The LKB1 protein expression was carried out by western blot analysis (B). The experiments were repeated 3 times. Data are presented as means ± SD (n = 3). * P<0.05 compared with only OA stimulation group.CC BY · PubMed Central

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  1. T Fukao, 2004, Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry., Prostaglandins, leukotrienes, and essential fatty acids, 70, 243, 10.1016/j.plefa.2003.11.001 · DOI

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Metadata

Authors
Niu, Y., Li, S., Na, L., Feng, R., Liu, L., Li, Y., & Sun, C.
Affiliations
Harbin Medical University (CN)
Corresponding author
Sun, Changhao
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-01-23
Volume
7
Issue
1
Pages
e30782
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0030782
PMC
PMC3264633
OpenAlex
W2073563008
Cited by
116
References
32
Citations by year
2026: 2 · 2025: 8 · 2024: 8 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 13 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 14 · 2014: 12 · 2013: 10 · 2012: 3
FWCI
30.39
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Natural Science Foundation of China (2010AA023002)
  • National High-tech Research and Development Program (2010AA023002)
  • National Institute on Alcohol Abuse and Alcoholism (K99AA023002, R00AA023002)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Mangiferin and Mango Extracts
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
mangiferin, plasma free fatty acids, AMPK, fatty acid degradation, hyperlipidemia, hepatic triglyceride accumulation, fatty acid uptake, fatty acid oxidation, CD36, carnitine palmitoyltransferase 1, DGAT2, acetyl-CoA carboxylase, metabolic syndrome, high-fat diet, oleic acid, beta-hydroxybutyrate
MeSH terms
Adenylate Kinase, Animals, Enzyme Activation, Fatty Acids, Nonesterified, Female, Humans, Hyperlipidemias, Hypoglycemic Agents, Liver, Male, Metabolism, Triglycerides, Down-Regulation, Rats, Wistar, Xanthones, Lipid Metabolism, Rats, Hep G2 Cells

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