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

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-β-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 PPARα, as well as a PPARα 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 PPARα transactivation, PPARα 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 PPARα activation were identified as possible mechanisms behind the observed effects on ApoA-I transcription.

• Authors: Jehad Z Tayyeb, Herman E Popeijus, Ronald P Mensink, Maurice C J M Konings, Kim H R Mulders, Jogchum Plat
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 120 Issue 10 Pg. 17219-17227 (10 2019) ISSN: 1097-4644 [Electronic] United States
• PMID: 31106471 (Publication Type: Journal Article)
• Copyright: © 2019 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.

Chemical References

• APOA1 protein, human
• Anti-Bacterial Agents
• Apolipoprotein A-I
• Fatty Acids, Volatile
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• PPAR alpha
• Amoxicillin
• CPT1A protein, human
• Carnitine O-Palmitoyltransferase

Topics

• Amoxicillin (pharmacology)
• Anti-Bacterial Agents (pharmacology)
• Apolipoprotein A-I (genetics, metabolism)
• Carnitine O-Palmitoyltransferase (genetics, metabolism)
• Fatty Acids, Volatile (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hepatoblastoma (drug therapy, metabolism, pathology)
• Humans
• In Vitro Techniques
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• Liver Neoplasms (drug therapy, metabolism, pathology)
• PPAR alpha (genetics, metabolism)
• Tumor Cells, Cultured