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Selective Inhibition of Organic Cation Transporter 1 by Benzoylpaeoniflorin Attenuates Hepatic Lipid Accumulation

Yajuan Bi1, Xue Wang2, Lifeng Han3

  • 1School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, People's Republic of China.

Journal of Natural Products
|December 23, 2022
PubMed

Insights

Researchers screened 200 natural products for inhibition of organic cation transporter 1 (OCT1), crucial for drug interactions and liver health. Benzoylpaeoniflorin emerged as a potent OCT1 inhibitor, showing promise for treating fatty liver disease.

Area of Science:

  • Pharmacology
  • Hepatology
  • Natural Products Chemistry

Background:

  • Organic cation transporter 1 (OCT1) is a liver-specific transporter involved in drug disposition and hepatic lipid metabolism.
  • OCT1 inhibition can influence drug-drug interactions and offers a potential therapeutic strategy for fatty liver diseases.

Purpose of the Study:

  • To systematically screen natural products for OCT1 inhibitory activity.
  • To identify selective OCT1 inhibitors for potential therapeutic applications in fatty liver disease.
  • To elucidate the mechanism of action of potent natural product inhibitors.

Main Methods:

  • High-throughput screening of 200 natural products for inhibition of OCT1-mediated 4,4-dimethylaminostyryl-N-methylpyridinium (ASP+) uptake.
  • In vitro uptake assays and in silico molecular docking to evaluate inhibitor selectivity against OCT2.
  • Hepatocyte-based assays to assess the effect of benzoylpaeoniflorin on lipid accumulation and related molecular pathways (AMPK, ACC, FASN).

Main Results:

  • Ten potent OCT1 inhibitors were identified from the natural product library.
  • Benzoylpaeoniflorin demonstrated the highest potency and selectivity for OCT1 over OCT2.
  • Benzoylpaeoniflorin reduced lipid accumulation in hepatocytes by activating AMPK and down-regulating lipogenic genes (ACC, FASN).

Conclusions:

  • Natural products represent a valuable source of selective OCT1 inhibitors.
  • Benzoylpaeoniflorin is a promising lead compound for developing therapies for fatty liver diseases.
  • Understanding OCT1-natural product interactions is crucial for predicting drug efficacy and toxicity.

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