Despite its beneficial properties, effects of betulinic acid on the nutrient-sensing mTOR pathway via insulin or IGF1 signaling remain unclear. Here, we investigated whether betulinic acid reduces intracellular lipid accumulation via the nutrient-sensing pathway in HepG2 cells. Results showed that betulinic acid reduced intracellular lipid accumulation in a dose-dependent manner and inhibited the expression of de novo lipogenesis-related genes and proteins. RNA sequencing analysis revealed the transcriptional modulation of plasma membrane proteins by betulinic acid, and an in silico binding assay indicated an interaction between betulinic acid and IR or IGF1R. Furthermore, betulinic acid downregulated the post-translational modification of the canonical IRS1/PI3K/AKT-pT308 and IGF1/mTORC2/AKT-pS473 pathways, thereby reducing the activity of the mTOR/S6K/S6 pathway. These findings imply that betulinic acid suppresses hepatic lipid synthesis by inhibiting insulin and IGF1 signaling as upstream effectors of the nutrient-sensing mTOR pathway and could be a potent nutraceutical agent for the treatment of metabolic syndromes.

中文翻译：

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桦木酸通过抑制胰岛素和 IGF1 信号作为营养感应 mTOR 通路的上游效应器来抑制从头脂肪生成

尽管桦木酸具有有益的特性，但通过胰岛素或 IGF1 信号传导对营养感应 mTOR 通路的影响仍不清楚。在这里，我们研究了桦木酸是否通过 HepG2 细胞中的营养感应途径减少细胞内脂质积累。结果表明，桦木酸以剂量依赖性方式减少细胞内脂质积累，并抑制从头脂肪生成相关基因和蛋白质的表达。RNA测序分析揭示了白桦脂酸对质膜蛋白的转录调节，以及计算机结合试验表明桦木酸与 IR 或 IGF1R 之间存在相互作用。此外，桦木酸下调经典 IRS1/PI3K/AKT-pT308 和 IGF1/mTORC2/AKT-pS473 通路的翻译后修饰，从而降低 mTOR/S6K/S6 通路的活性。这些发现表明，桦木酸通过抑制胰岛素和 IGF1 信号作为营养感应 mTOR 通路的上游效应物来抑制肝脏脂质合成，并且可能是治疗代谢综合征的有效营养剂。