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1.
Int J Mol Sci ; 20(23)2019 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-31783518

RESUMEN

In a recent human study, we observed that amoxicillin treatment decreased HDL-C concentration. We hypothesize that antibiotics lower the transcription and secretion of ApoA-I, the responsible protein for HDL production. HepG2 and Caco-2 cells were exposed to increasing dose of amoxicillin, penicillin, and streptomycin. Secreted ApoA-I protein and mRNA transcripts were analyzed using ELISA and qPCR, respectively. To unravel underlying mechanisms, KEAP1, CPT1, and CHOP mRNA expressions were determined as well as PPARα transactivation. In HepG2 and Caco-2, amoxicillin decreased ApoA-I transcription and secretion. Effects on ApoA-I expression were clearly there for amoxicillin while no effects were observed for penicillin or streptomycin. KEAP1, CPT1, and CHOP mRNA expressions were reduced by amoxicillin treatments. Moreover, a significant correlation between ApoA-I and CPT1 mRNA expressions was found. Furthermore, amoxicillin lowered PPARα transactivation. All together, these data suggest that inhibited PPARα transactivation is involved in the effects of amoxicillin on ApoA-I. In conclusion, the direct effect of amoxicillin in treated HepG2 and Caco-2 cells was a lower ApoA-I secretion and transcription. Based on evaluating alterations in KEAP1, CPT1, and CHOP mRNA expressions plus PPARα transactivation, we suggest that a reduced PPARα activation is a potential mechanism behind the observed amoxicillin effects on ApoA-I expression.


Asunto(s)
Amoxicilina/farmacología , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , PPAR alfa/genética , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Células CACO-2 , Carnitina O-Palmitoiltransferasa/genética , Línea Celular Tumoral , Células Hep G2 , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , ARN Mensajero/genética , Factor de Transcripción CHOP/genética
2.
J Cell Biochem ; 120(10): 17219-17227, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31106471

RESUMEN

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-ß-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.


Asunto(s)
Apolipoproteína A-I/metabolismo , Ácidos Grasos Volátiles/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hepatoblastoma/metabolismo , Neoplasias Hepáticas/metabolismo , Amoxicilina/farmacología , Antibacterianos/farmacología , Apolipoproteína A-I/genética , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/patología , Humanos , Técnicas In Vitro , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , PPAR alfa/genética , PPAR alfa/metabolismo , Células Tumorales Cultivadas
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