Ginsenoside Rg1 exerts antidepressant effect by regulating hepatic kynurenine metabolism through promoting the interaction between HNF4α and PGC1α

IF 6.8 2区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Ginseng Research Pub Date : 2024-12-04 DOI:10.1016/j.jgr.2024.12.002

Keke Jia , Shuman Pan , Wenyuan Wu , Yiming Sun , Qingyu Zhang

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Abstract

Background

The neuroprotective effect of ginsenoside Rg1 is indeed one of the current research hotspots. However, its limited ability to cross the blood-brain barrier results in low distribution within the brain. Thus, the mechanism through which ginsenoside Rg1 affects the central nervous system needs further examination.

Methods

The LC-MS/MS analysis was used to detect the Kyn level. The expression of kynurenine aminotransferase 2 (KAT2) and kynurenine 3-monooxygenase (KMO) were investigated by qRT-PCR and western blotting analysis. The interaction between the transcription factor hepatocyte nuclear factor-4α (HNF4α) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) was explored by Co-IP assay. The HNF4α binding sites in the KAT2 and KMO genes were analyzed by ChIP. In addition, we specifically knocked down HNF4α in the liver of mice by injecting adeno-associated virus into the tail vein.

Results

Ginsenoside Rg1 upregulated the expression of KAT2 and KMO, thereby increasing the metabolism of Kyn in the liver. Further exploring its mechanism, we discovered that ginsenoside Rg1 increased the expression of KAT2 and KMO by promoting the interaction between the transcription factor HNF4α and PGC1α. Hepatic HNF4α knockdown abolished the antidepressant effects induced by ginsenoside Rg1.

Conclusion

Our findings reveal a novel mechanism in which ginsenoside Rg1 upregulates KAT2 and KMO through the HNF4α/PGC1α pathway, reducing hepatic Kyn levels and subsequently alleviating depression.

Abstract Image

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人参皂苷Rg1通过促进HNF4α和PGC1α的相互作用，调节肝脏犬尿氨酸代谢，发挥抗抑郁作用

人参皂苷Rg1的神经保护作用确实是当前研究的热点之一。然而，它穿过血脑屏障的能力有限，导致其在大脑内的分布很低。因此，人参皂苷Rg1影响中枢神经系统的机制有待进一步研究。方法采用LC-MS/MS法检测Kyn含量。采用qRT-PCR和western blotting检测犬尿氨酸转氨酶2 （KAT2）和犬尿氨酸3-单加氧酶（KMO）的表达。采用Co-IP法探讨转录因子肝细胞核因子-4α (HNF4α)与过氧化物酶体增殖物激活受体-γ共激活因子-1α (PGC1α)之间的相互作用。用ChIP分析KAT2和KMO基因中的HNF4α结合位点。此外，我们通过向小鼠尾静脉注射腺相关病毒特异性地敲除了小鼠肝脏中的HNF4α。结果人参皂苷Rg1上调KAT2和KMO的表达，从而增加肝脏中Kyn的代谢。进一步探索其作用机制，我们发现人参皂苷Rg1通过促进转录因子HNF4α和PGC1α的相互作用而增加KAT2和KMO的表达。肝脏HNF4α敲低可消除人参皂苷Rg1诱导的抗抑郁作用。结论人参皂苷Rg1通过HNF4α/PGC1α通路上调KAT2和KMO，从而降低肝脏Kyn水平，从而缓解抑郁的新机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Ginseng Research CHEMISTRY, MEDICINAL-INTEGRATIVE & COMPLEMENTARY MEDICINE

CiteScore

11.40

自引率

9.50%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Journal of Ginseng Research (JGR) is an official, open access journal of the Korean Society of Ginseng and is the only international journal publishing scholarly reports on ginseng research in the world. The journal is a bimonthly peer-reviewed publication featuring high-quality studies related to basic, pre-clinical, and clinical researches on ginseng to reflect recent progresses in ginseng research. JGR publishes papers, either experimental or theoretical, that advance our understanding of ginseng science, including plant sciences, biology, chemistry, pharmacology, toxicology, pharmacokinetics, veterinary medicine, biochemistry, manufacture, and clinical study of ginseng since 1976. It also includes the new paradigm of integrative research, covering alternative medicinal approaches. Article types considered for publication include review articles, original research articles, and brief reports. JGR helps researchers to understand mechanisms for traditional efficacy of ginseng and to put their clinical evidence together. It provides balanced information on basic science and clinical applications to researchers, manufacturers, practitioners, teachers, scholars, and medical doctors.