Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Barcelona, Spain.
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain.
Cell Commun Signal. 2024 May 28;22(1):297. doi: 10.1186/s12964-024-01666-y.
Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD()-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins.
Rats fed with fructose in drinking water, Sirt1 mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used.
Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1 mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin.
Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.
内质网（ER）应激介导的极低密度脂蛋白（VLDL）受体（VLDLR）在肝脏水平的增加通过增加富含甘油三酯的脂蛋白向肝脏的输送来促进肝脂肪变性。在这里，我们研究了 NAD（-）依赖性去乙酰化酶 Sirtuin 1（SIRT1）是否通过调节 VLDLR 水平和随后富含甘油三酯的脂蛋白的摄取来调节肝脂质积累。
用含果糖的饮用水喂养大鼠、Sirt1 小鼠、用 ER 应激剂衣霉素处理的 Sirt1 激活剂或没有 Sirt1 激活剂的小鼠以及用 siRNA 转染或用衣霉素或不同抑制剂处理的人 Huh-7 肝癌细胞。
在由果糖饮用水诱导的代谢功能障碍相关脂肪性肝病（MASLD）大鼠模型中，肝 SIRT1 蛋白水平降低，而 VLDLR 水平上调。此外，Sirt1 小鼠表现出肝 VLDLR 水平升高，这与 ER 应激无关，但伴随着缺氧诱导因子 1α（HIF-1α）靶基因的表达增加。SIRT1 的药理学抑制或基因敲低可上调人 Huh-7 肝癌细胞系中 VLDLR 蛋白水平，而 HIF-1α 的药理学抑制可消除这种增加。最后，SIRT1 激活可防止 ER 应激剂衣霉素处理的小鼠肝 VLDLR 蛋白水平升高。
总之，这些发现表明 SIRT1 通过调节肝 VLDLR 水平来减轻脂肪肝的发展。
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