Short-Chain Fatty Acids (Except Hexanoic Acid) Lower NF-kB Transactivation, Which Rescues Inflammation-Induced Decreased Apolipoprotein A-I Transcription in HepG2 Cells.

Abstract

Concentrations of apolipoprotein A-I (ApoA-I) decrease during inflammation, which may lead to dysfunctional ApoA-I-poor high-density lipoprotein (HDL) particles, and as such, elevate cardiovascular risk. Therefore, rescuing ApoA-I concentrations, especially during inflammation, seems beneficial. Recently, short-chain fatty acids (SCFAs) have received more attention as a strategy in reversing atherosclerosis. We here evaluated the effects of SCFAs on inflammatory pathways in relation to ApoA-I transcription. SCFAs dose-response studies were performed in the presence and absence of inflammatory cytokines. ApoA-I and interleukin 8 (IL-8) mRNA expression were analyzed using qPCR and ELISA, respectively. To study underlying mechanisms, nuclear factor kappa B (NF-κB) transactivation and changes in mRNA expressions of the genes targets of bromodomain and extra-terminal (BET) inhibition, peroxisome proliferator-activated receptor-alpha (PPARα) transactivation and activator protein 1 (AP-1) pathway were analyzed. SCFAs (except hexanoic acid) increased ApoA-I mRNA transcription in both normal and inflammatory conditions and lowered IL-8 mRNA expression. This anti-inflammatory effect of SCFAs was confirmed by inhibition of NF-κB transactivation. Moreover, butyric acid increased carnitine palmitoyltransferase 1 (CPT1), PPARα target gene, mRNA transcription in both conditions, and there was a negative correlation between CPT1 and NF-κB. Therefore, PPARα transactivation is probably involved in the anti-inflammatory effects of SCFAs, which rescues ApoA-I transcription. In conclusion, propionate, butyrate and valerate elicit anti-inflammatory effects which might rescue ApoA-I transcription in inflammatory conditions via PPARα transactivation mediated NF-κB inhibition.

• Authors: Jehad Z Tayyeb, Herman E Popeijus, Ronald P Mensink, Maurice C J M Konings, Fatma B A Mokhtar, Jogchum Plat
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 14 (Jul 18 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32708494 (Publication Type: Journal Article)

Chemical References

• Apolipoprotein A-I
• Butyrates
• Caproates
• Fatty Acids, Volatile
• I-kappa B Proteins
• Interleukin-8
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• PPAR alpha
• PPARA protein, human
• Propionates
• Proto-Oncogene Proteins c-fos
• Proto-Oncogene Proteins c-jun
• Valerates
• hexanoic acid
• CPT1A protein, human
• Carnitine O-Palmitoyltransferase

Topics

• Apolipoprotein A-I (genetics, metabolism)
• Butyrates (pharmacology)
• Caproates (pharmacology)
• Carnitine O-Palmitoyltransferase (metabolism)
• Fatty Acids, Volatile (pharmacology)
• Hep G2 Cells
• Humans
• I-kappa B Proteins (genetics, metabolism)
• Inflammation (genetics, metabolism)
• Interleukin-8 (genetics, metabolism)
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• PPAR alpha (metabolism)
• Propionates (pharmacology)
• Proto-Oncogene Proteins c-fos (genetics, metabolism)
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Transcriptional Activation (drug effects)
• Valerates (pharmacology)