title: Monascin and ankaflavin act as natural AMPK activators with PPARα agonist activity to down-regulate nonalcoholic steatohepatitis in high-fat diet-fed C57BL/6 mice.
abstract: Yellow pigments monascin (MS) and ankaflavin (AK) are secondary metabolites derived from Monascus-fermented products. The hypolipidemic and anti-inflammatory effects of MS and AK indicate that they have potential on preventing or curing nonalcoholic fatty liver disease (NAFLD). Oleic acid (OA) and high-fat diet were used to induce steatosis in FL83B hepatocytes and NAFLD in mice, respectively. We found that both MS and AK prevented fatty acid accumulation in hepatocytes by inhibiting fatty acid uptake, lipogenesis, and promoting fatty acid beta-oxidation mediated by activating peroxisome proliferator-activated receptor (PPAR)-α and AMP-activated kinase (AMPK). Furthermore, MS and AK significantly attenuated high-fat diet-induced elevation of total cholesterol (TC), triaceylglycerol (TG), free fatty acid (FFA), and low density lipoprotein-cholesterol (LDL-C) in plasma. MS and AK promoted AMPK phosphorylation, suppressed the steatosis-related mRNA expression and inflammatory cytokines secretion, as well as upregulated farnesoid X receptor (FXR), peroxisome proliferator-activated receptor gamma co-activator (PGC)-1α, and PPARα expression to induce fatty acid oxidation in the liver of mice. We provided evidence that MS and AK act as PPARα agonists to upregulate AMPK activity and attenuate NAFLD. MS and AK may be supplied in food supplements or developed as functional foods to reduce the risk of diabetes and obesity.
authors.affiliation: Department of Biochemical Science & Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Wei-Hsuan
authors.initials: WH
authors.lastname: Hsu
authors.affiliation: Department of Biochemical Science & Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Ting-Hung
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Department of Biochemical Science & Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Bao-Hong
authors.initials: BH
authors.lastname: Lee
authors.affiliation: R&D Division, SunWay Biotechnology Company Limited, Taipei, Taiwan.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Hsu
authors.affiliation: Department of Biochemical Science & Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan. Electronic address: tmpan@ntu.edu.tw.
authors.forename: Tzu-Ming
authors.initials: TM
authors.lastname: Pan
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D015536:Down-Regulation; D020536:Enzyme Activators / Q000494:pharmacology*; D005234:Fatty Liver / Q000378:metabolism*; D005415:Flavins / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D047493:PPAR alpha / Q000819:agonists*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D020536:Enzyme Activators; D005415:Flavins; D006575:Heterocyclic Compounds, 3-Ring; D047493:PPAR alpha; C499916:ankaflavin; D000263:Adenylate Kinase; C517880:monascin
keywords: ACC; ACOX; ACS; AK; ALT; AMP-activated kinase; AMPK; AST; Ankaflavin (AK); BSA; CPT-1; CV; DMSO; ELISA; FABP; FAS; FAT; FBS; FFA; FXR; GLUT; H&E; HAECs; HDL-C; HPLC; HUVECs; IACUC; ICAM-1; IL-6; Institutional Animal Care and Use Committee; JNK; LDL-C; MS; MTP; Monascin (MS); NAFLD; NASH; NCBI; NF-κB; National Center for Biotechnology Information; Nonalcoholic fatty liver disease (NAFLD); Nrf2; OA; Oleic acid (OA); PCR; PGC-1α; PPARα; PPARγ; PPREs; PTP1B; Peroxisome proliferator-activated receptor (PPAR)-α; SDS; SPPARMs; SREBP-1c; TC; TG; TGFβ; TLC; TNF-α; TR-FRET; TZDs; Tyr; VCAM-1; acetyl-CoA carboxylase; acyl-CoA oxidase; acyl-CoA synthetase; alanine aminotranferase; ankaflavin; aspartate transaminase; bovine serum albumin; c-Jun NH(2)-terminal kinase; cardiovascular; carnitine palmitoyl transferase I; dimethyl sulfoxide; enzyme-linked immunosorbent assay; farnesoid X receptor; fatty acid synthase; fatty acid transporter; fatty acid-binding protein; fetal bovine serum; free fatty acid; glucose transporter; hematoxylin and eosin; high-density lipoprotein cholesterol; high-performance liquid chromatography; human aortic endothelial cells; human umbilical vein endothelial cells; iNOS; inducible nitric oxide synthase; intercellular adhesion molecule-1; interleukin-6; low density lipoprotein-cholesterol; microsomal triglyceride transfer protein; monascin; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; nuclear factor erythroid 2-related factor 2; nuclear factor-kappaB; oleic acid; peroxisome proliferator activated receptor alpha; peroxisome proliferator activated receptor gamma; peroxisome proliferator-activated receptor gamma co-activator 1-alpha; peroxisome-proliferator-response elements; polymerase chain reaction; protein tyrosine phosphatase 1B; selective PPAR modulators; sodium dodecyl sulfate; sterol regulatory element-binding protein; thiazolidinediones; thin layer chromatography; time-resolved fluorescence resonance energy transfer; total cholesterol; transformation growth factor beta; triaceylglycerol; tumor necrosis factor-alpha; tyrosine; vascular cell adhesion molecule-1