Search

Peroxisome proliferator-activated receptors (PPARs) have been suggested to play crucial roles in the pathology of NAFLD with a vague understanding of the underlying mechanism. Here, we integrated large-scale literature data and clinical data to explore the potential role of the PPAR-APOA1 signaling pathway in the pathology of NAFLD. First, the signaling pathway connecting PPARs, APOA1, and NAFLD was constructed. Then, we employed clinical data to explore the association between APOA1 levels and NAFLD. In addition, we built the APOA1-driven pathway analysis to explore the potential mechanism of the APOA1-NAFLD association. Pathway analysis showed that APOA1 serves as a hubprotein connecting PPARs and NAFLD through a beneficial modulation of 16 out of 21 NAFLD upstream regulators. Each relationship within the composed pathway was supported by results from multiple previous studies. Clinical data analysis showed that an increase of APOA1 level was associated with a significantly decreased NAFLD prevalence ( χ 2 = 292.109; P < 0.001). When other confounding factors were adjusted, serum APOA1 level was shown as an independent risk factor for the prevalence of NAFLD ( P value<.0001; OR = 0.562). Our results suggested that the three PPARs (PPARA, PPARD, and PPARG) might promote the expression and molecular transportation of APOA1 to form a PPAR-APOA1 signaling pathway that demonstrated a beneficial role in the pathogenesis of NAFLD., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2022 Changxi Chen et al.)

Ketoconazole (KTZ), a clinical antifungal agent, is a known inhibitor of CYP3A and permeability glycoprotein (P-gp). Berberine (BBR), a natural plant-derived product used for gastroenteritis, is a substrate of P-gp. Recently, a synergistic antifungal effect of KTZ combined with BBR has been revealed. In this study, we performed both in vivo and in vitro experiments to explore whether pharmacokinetic interactions between KTZ and BBR would benefit their pharmacodynamic synergism. After oral co-administration of 10 mg/kg KTZ with 60 mg/kg BBR, the average area under the curve (AUC) and the maximum concentration (C(max) ) for KTZ increased to 215% and 449% (p < 0.05), respectively, in male rats and 157% and 172% (p < 0.05), respectively, in female rats, compared with those administered KTZ alone. Area under the curve and C(max) for BBR increased to 173% and 142%, respectively, compared with those administered BBR alone. After intravenous co-administration of 0.5 mg/kg KTZ and 0.8 mg/kg BBR, the pharmacokinetic properties of KTZ remained the same, but AUC of BBR increased to 254% (p < 0.05) compared with those administered BBR alone. In rat liver microsomes, inhibitory concentration (IC)(50) of BBR inhibiting KTZ depletion was determined to be 103 µm. These resulting pharmacokinetic interactions may benefit their pharmacodynamic synergism to a certain extent., (Copyright © 2011 John Wiley & Sons, Ltd.)