Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy (Q.S., Y.G., F.H.), Departments of Pharmacology (W.H., S.W., Y.L., Z.Q.) and Medicinal Chemistry, School of Pharmacy (P.X., Z.L.), School of Basic Medical Sciences and Clinical Pharmacy (M.Z.), and National Experimental Teaching Demonstration Center of Pharmacy, School of Pharmacy (N.L.), China Pharmaceutical University, Nanjing, China; Shimadzu (China) Co., LTD., Nanjing Branch, Nanjing, China (H.M.); and College of Pharmacy, Shenzhen Technology University, Shenzhen, China (H.L.).
Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy (Q.S., Y.G., F.H.), Departments of Pharmacology (W.H., S.W., Y.L., Z.Q.) and Medicinal Chemistry, School of Pharmacy (P.X., Z.L.), School of Basic Medical Sciences and Clinical Pharmacy (M.Z.), and National Experimental Teaching Demonstration Center of Pharmacy, School of Pharmacy (N.L.), China Pharmaceutical University, Nanjing, China; Shimadzu (China) Co., LTD., Nanjing Branch, Nanjing, China (H.M.); and College of Pharmacy, Shenzhen Technology University, Shenzhen, China (H.L.)
Drug Metab Dispos. 2023 Dec;51(12):1628-1641. doi: 10.1124/dmd.123.001449. Epub 2023 Sep 8.
The hepatic SLC13A5/SLC25A1-ATP-dependent citrate lyase (ACLY) signaling pathway, responsible for maintaining the citrate homeostasis, plays a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Bempedoic acid (BA), an ACLY inhibitor commonly used for managing hypercholesterolemia, has shown promising results in addressing hepatic steatosis. This study aimed to elucidate the intricate relationships in processes of hepatic lipogenesis among SLC13A5, SLC25A1, and ACLY and to examine the therapeutic potential of BA in NAFLD, providing insights into its underlying mechanism. In murine primary hepatocytes and HepG2 cells, the silencing or pharmacological inhibition of SLC25A1/ACLY resulted in significant upregulation of SLC13A5 transcription and activity. This increase in SLC13A5 activity subsequently led to enhanced lipogenesis, indicating a compensatory role of SLC13A5 when the SLC25A1/ACLY pathway was inhibited. However, BA effectively counteracted this upregulation, reduced lipid accumulation, and ameliorated various biomarkers of NAFLD. The disease-modifying effects of BA were further confirmed in NAFLD mice. Mechanistic investigations revealed that BA could reverse the elevated transcription levels of SLC13A5 and ACLY, and the subsequent lipogenesis induced by PXR activation in vitro and in vivo. Importantly, this effect was diminished when PXR was knocked down, suggesting the involvement of the hepatic PXR-SLC13A5/ACLY signaling axis in the mechanism of BA action. In conclusion, SLC13A5-mediated extracellular citrate influx emerges as an alternative pathway to SLC25A1/ACLY in the regulation of lipogenesis in hepatocytes, BA exhibits therapeutic potential in NAFLD by suppressing the hepatic PXR-SLC13A5/ACLY signaling axis, while PXR, a key regulator in drug metabolism may be involved in the pathogenesis of NAFLD. SIGNIFICANCE STATEMENT: This work describes that bempedoic acid, an ATP-dependent citrate lyase (ACLY) inhibitor, ameliorates hepatic lipid accumulation and various hallmarks of non-alcoholic fatty liver disease. Suppression of hepatic SLC25A1-ACLY pathway upregulates SLC13A5 transcription, which in turn activates extracellular citrate influx and the subsequent DNL. Whereas in hepatocytes or the liver tissue challenged with high energy intake, bempedoic acid reverses compensatory activation of SLC13A5 via modulating the hepatic PXR-SLC13A5/ACLY axis, thereby simultaneously downregulating SLC13A5 and ACLY.
肝脏 SLC13A5/SLC25A1-ATP 依赖性柠檬酸裂解酶 (ACLY) 信号通路负责维持柠檬酸稳态，在非酒精性脂肪性肝病 (NAFLD) 的发病机制中起着关键作用。贝美前列素 (BA) 是一种常用于治疗高胆固醇血症的 ACLY 抑制剂，在治疗肝脂肪变性方面显示出有前景的结果。本研究旨在阐明 SLC13A5、SLC25A1 和 ACLY 之间肝内脂肪生成过程中的复杂关系，并研究 BA 在 NAFLD 中的治疗潜力，为其潜在机制提供见解。在鼠原代肝细胞和 HepG2 细胞中，SLC25A1/ACLY 的沉默或药理学抑制导致 SLC13A5 转录和活性的显著上调。这种 SLC13A5 活性的增加随后导致脂肪生成增强，表明当 SLC25A1/ACLY 途径被抑制时，SLC13A5 发挥代偿作用。然而，BA 可有效拮抗这种上调，减少脂质堆积，并改善 NAFLD 的各种生物标志物。BA 在 NAFLD 小鼠中的疾病改善作用得到了进一步证实。机制研究表明，BA 可以逆转体外和体内 PXR 激活诱导的 SLC13A5 和 ACLY 转录水平升高以及随后的脂肪生成。重要的是，当 PXR 被敲低时，这种作用会减弱，这表明肝脏 PXR-SLC13A5/ACLY 信号轴参与了 BA 作用的机制。总之，SLC13A5 介导的细胞外柠檬酸流入作为 SLC25A1/ACLY 调节肝细胞脂肪生成的替代途径出现，BA 通过抑制肝脏 PXR-SLC13A5/ACLY 信号轴在 NAFLD 中具有治疗潜力，而 PXR 作为药物代谢的关键调节剂可能参与 NAFLD 的发病机制。
本研究描述了贝美前列素，一种 ATP 依赖性柠檬酸裂解酶 (ACLY) 抑制剂，可改善肝脂质堆积和非酒精性脂肪性肝病的各种特征。抑制肝 SLC25A1-ACLY 通路可上调 SLC13A5 的转录，进而激活细胞外柠檬酸流入和随后的 DNL。然而，在高能量摄入挑战的肝细胞或肝组织中，贝美前列素通过调节肝脏 PXR-SLC13A5/ACLY 轴来逆转 SLC13A5 的代偿性激活，从而同时下调 SLC13A5 和 ACLY。
