The effects of short-chain fatty acids on the transcription and secretion of apolipoprotein A-I in human hepatocytes in vitro

Jehad Z. Tayyeb, Herman E. Popeijus, Ronald P. Mensink, Maurice C. J. M. Konings, Kim H. R. Mulders, Jogchum Plat*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Web of Science)

Abstract

Background Apolipoprotein-I (ApoA-I), the major component of high-density lipoprotein (HDL) particles, mediates cholesterol efflux by which it facilitates the removal of excess cholesterol from peripheral tissues. Therefore, elevating ApoA-I production leading to the production of new pre-beta-HDL particles is thought to be beneficial in the prevention of cardiovascular diseases. Recently, we observed that amoxicillin treatment led to decreased HDL concentrations in healthy human volunteers. We questioned whether this antibiotic effect was directly or indirectly, via changed short-chain fatty acids (SCFA) concentrations through an altered gut microflora. Therefore, we here evaluated the effects of amoxicillin and various SCFA on hepatic ApoA-I expression, secretion, and the putative underlying pathways. Methods and Results Human hepatocytes (HepG2) were exposed to increasing dose of amoxicillin or SCFA for 48 hours. ApoA-I messenger RNA (mRNA) transcription and secreted protein were analyzed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. To study underlying mechanisms, changes in mRNA expression of KEAP1, CPT1, and PPAR alpha, as well as a PPAR alpha transactivation assay, were analyzed. Amoxicillin dose-dependently decreased ApoA-I mRNA transcription as well as ApoA-I protein secretion. SCFA treatment resulted in a dose-dependent stimulation of ApoA-I mRNA transcription, however, the ApoA-I protein secretion was decreased. Furthermore, SCFA treatment increased PPAR alpha transactivation, PPAR alpha and CPT1 mRNA transcription, whereas KEAP1 mRNA transcription was decreased. Conclusion Direct treatment of HepG2 cells with amoxicillin has either direct effects on lowering ApoA-I transcription and secretion or indirect effects via modified SCFA concentrations because SCFA were found to stimulate hepatic ApoA-I expression. Furthermore, BET inhibition and PPAR alpha activation were identified as possible mechanisms behind the observed effects on ApoA-I transcription.

Original languageEnglish
Pages (from-to)17219-17227
Number of pages9
JournalJournal of Cellular Biochemistry
Volume120
Issue number10
DOIs
Publication statusPublished - Oct 2019

Keywords

  • antibiotics
  • ApoA-I
  • BET
  • PPAR alpha
  • SCFA
  • transcription
  • ACTIVATED RECEPTOR-ALPHA
  • PPAR-ALPHA
  • GENE-EXPRESSION
  • GUT MICROBIOTA
  • BETA-LACTAM
  • SUPPLEMENTATION
  • ANTIBIOTICS
  • AMOXICILLIN
  • MECHANISMS
  • HEALTH

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