Methyl protodioscin increases ABCA1 expression and cholesterol efflux while inhibiting gene expressions for synthesis of cholesterol and triglycerides by suppressing SREBP transcription and microRNA 33a/b levels

Atherosclerosis. 2015 Apr;239(2):566-70. doi: 10.1016/j.atherosclerosis.2015.02.034. Epub 2015 Feb 23.

Abstract

Sterol regulatory element-binding proteins (SREBPs) regulate homeostasis of LDL, HDL and triglycerides. This study was aimed to determine if inhibition of SREBPs by methyl protodioscin (MPD) regulates downstream gene and protein expressions of lipid metabolisms. In THP-1 macrophages, MPD increases levels of ABCA1 mRNA and protein in dose- and time-dependent manners, and apoA-1-mediated cholesterol efflux. The underlying mechanisms for the effects is that MPD inhibits the transcription of SREBP1c and SREBP2, and decreases levels of microRNA 33a/b hosted in the introns of SREBPs, which leads to reciprocally increase ABCA1 levels. In HepG2 cells, MPD shows the same effects as these observed in THP-1 macrophages. MPD also decreases the gene expressions of HMGCR, FAS and ACC for cholesterol and fatty acid synthesis. MPD further promotes LDL receptor through reducing the PCSK9 level. Collectively, the study demonstrates that MPD potentially increase HDL cholesterol while reducing LDL cholesterol and triglycerides.

Keywords: ABCA1; HDL; LDL; Methyl protodioscin; SREBP; miR-33a/b.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism*
  • Cholesterol / metabolism*
  • Diosgenin / analogs & derivatives*
  • Diosgenin / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Foam Cells / drug effects*
  • Foam Cells / metabolism
  • Hep G2 Cells
  • Humans
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / genetics
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Proprotein Convertase 9
  • Proprotein Convertases / metabolism
  • RNA, Messenger / metabolism
  • Saponins / pharmacology*
  • Serine Endopeptidases / metabolism
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism*
  • Time Factors
  • Transcription, Genetic*
  • Triglycerides / metabolism*
  • Up-Regulation

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • MIRN33a microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • SREBF1 protein, human
  • SREBF2 protein, human
  • Saponins
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Triglycerides
  • methyl protodioscin
  • Cholesterol
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases
  • Diosgenin