Abstract
BackgroundApolipoprotein‐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 ResultsHuman 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.ConclusionDirect 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.
Highlights
Several studies have suggested that antibiotics affect lipid and lipoprotein metabolism.[1,2] in a recent placebo‐controlled trial we observed that amoxicillin treatment for 7 days lowered high‐density lipoprotein (HDL) cholesterol concentrations in healthy volunteers.[2]
We here report a series of in vitro experiments in HepG2 cells supporting our hypothesis that antibiotics could have direct and indirect effects on hepatic ApoA‐I transcription and secretion
We showed that amoxicillin lowered ApoA‐I transcription and secretion by HepG2 cells, whereas all short‐chain fatty acids (SCFA) tested, which are metabolites produced by microbiota, clearly increased ApoA‐I transcription, except for C4 at higher concentrations
Summary
Several studies have suggested that antibiotics affect lipid and lipoprotein metabolism.[1,2] in a recent placebo‐controlled trial we observed that amoxicillin treatment for 7 days lowered high‐density lipoprotein (HDL) cholesterol concentrations in healthy volunteers.[2]. Human hepatocellular liver carcinoma (HepG2) cells.[11,12] BET inhibitors can bind to BET proteins such as BRD4, a general transcriptional regulator, which can regulate transcription of target genes such as KEAP1.13,14 PPARα is a nuclear receptor that forms a heterodimer with the retinoid X receptor, which binds to specific response elements (PPREs) within promoter regions of target genes such as PPARα itself, CPT1,15 and ApoA‐I.16 Various dietary components such as long‐chain fatty acids have been recognized as natural ligands for PPARα,[17] but there are indications that SCFA may have similar effects.[18,19] except for effects on changes in ApoA‐I messenger RNA (mRNA), we evaluated changes in KEAP1, CPT1, and PPARα mRNA expressions during exposure of HepG2 cells to different SCFA to examine potential underlying pathways Human hepatocellular liver carcinoma (HepG2) cells.[11,12] BET inhibitors can bind to BET proteins such as BRD4, a general transcriptional regulator, which can regulate transcription of target genes such as KEAP1.13,14 PPARα is a nuclear receptor that forms a heterodimer with the retinoid X receptor, which binds to specific response elements (PPREs) within promoter regions of target genes such as PPARα itself, CPT1,15 and ApoA‐I.16 Various dietary components such as long‐chain fatty acids have been recognized as natural ligands for PPARα,[17] but there are indications that SCFA may have similar effects.[18,19] except for effects on changes in ApoA‐I messenger RNA (mRNA), we evaluated changes in KEAP1, CPT1, and PPARα mRNA expressions during exposure of HepG2 cells to different SCFA to examine potential underlying pathways
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