Dapagliflozin modulates hepatic lipid metabolism through the proprotein convertase subtilisin/kexin type 9/low density lipoprotein receptor pathway

IF 5.7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes, Obesity & Metabolism Pub Date : 2025-01-20 DOI:10.1111/dom.16202

Fengyuan Lu MD, En Li MD, Yifeng Gao MD, Yan Zhang PhD, Lijuan Kong MD, Xiaoyu Yang PhD

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Abstract

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly secreted by the liver, and plays a crucial role in lipid metabolism disorder. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) can regulate lipid metabolism through various pathways, including reducing visceral fat accumulation, modulating serum lipoprotein levels and alleviating hepatic steatosis. However, the specific regulatory mechanisms remain unclear.

Methods

We built a model of glucose and lipid metabolism disorder in vivo and in vitro, and explored the regulatory mechanism of dapagliflozin in regulating liver lipid metabolism.

Results

We found that the SGLT2i dapagliflozin significantly reduced serum levels of PCSK9, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice, while also improving hepatic steatosis. In vitro studies confirmed that dapagliflozin increased LDL receptor (LDLR) expression in HepG2 cells, enhancing their ability to uptake LDL-C.

Conclusions

Further mechanistic studies revealed that the hepatocyte nuclear factor-1-alpha (HNF1α)/PCSK9/LDLR signalling pathway may be involved in dapagliflozin's regulation of lipid metabolism homeostasis.

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达格列净通过蛋白转化酶枯草杆菌素/kexin 9型/低密度脂蛋白受体途径调节肝脏脂质代谢。

背景：蛋白转化酶枯草素/酶解蛋白9型（PCSK9）主要由肝脏分泌，在脂质代谢紊乱中起重要作用。钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）可以通过多种途径调节脂质代谢，包括减少内脏脂肪堆积、调节血清脂蛋白水平和减轻肝脏脂肪变性。然而，具体的监管机制尚不清楚。方法：建立体内外糖脂代谢紊乱模型，探讨达格列净对肝脏脂质代谢的调节机制。结果：我们发现SGLT2i达格列净显著降低高脂饮食（HFD）喂养小鼠血清PCSK9、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）水平，同时改善肝脏脂肪变性。体外研究证实，达格列净可增加HepG2细胞中LDL受体（LDLR）的表达，增强其摄取LDL- c的能力。结论：进一步的机制研究表明，肝细胞核因子-1- α (HNF1α)/PCSK9/LDLR信号通路可能参与了达格列净对脂质代谢稳态的调节。

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

Diabetes, Obesity & Metabolism 医学-内分泌学与代谢

CiteScore

10.90

自引率

6.90%

发文量

319

审稿时长

3-8 weeks

期刊介绍： Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.