Endogenous hydrogen sulfide (H₂S) affects cholesterol homeostasis and liver X receptor α (LXRα) expression. However, whether low density lipoprotein (LDL) receptor (LDLR), a key player in cholesterol homeostasis, is regulated by exogenous H₂S through LXRα signaling has not been determined. We investigated the effects of sodium hydrosulfide (NaHS, H₂S donor) on LDLR expression in the presence or absence of LXR agonists, T0901317 or GW3965 in HepG2 cells. We found that H₂S strongly accumulated LDLR precursor in the presence of T0901317. Hence LDLR transcription and the genes involved in LDLR precursor maturation and degradation were studied. T0901317 increased the LDLR mRNA level, while H₂S didn't affect LDLR transcription. H₂S had no significant effect on the expression of LXRα and inducible degrader of LDLR (IDOL). H₂S and T0901317 altered mRNA levels of several enzymes for N- and O-glycosylation and endoplasmic reticulum (ER) chaperones assisting LDLR maturation, but didn't affect their protein levels. H₂S decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) protein levels and its mRNA level elevated by T0901317. T0901317 with PCSK9 siRNA also accumulated LDLR precursor as did T0901317 with H₂S. High glucose increased PCSK9 protein levels and attenuated LDLR precursor accumulation induced by T0901317 with H₂S. Taken together, H₂S accumulates LDLR precursor by downregulating PCSK9 expression but not through the LXRα-IDOL pathway, LDLR transcriptional activation or dysfunction of glycosylation enzymes and ER chaperones. These results also indicate that PCSK9 plays an important role in LDLR maturation in addition to its well-known effect on the degradation of LDLR mature form.

中文翻译：

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硫化氢通过下调 HepG2 细胞中的 PCSK9 来积累 LDL 受体前体。

内源性硫化氢 (H ₂ S) 影响胆固醇稳态和肝脏 X 受体 α (LXRα) 表达。然而，尚未确定胆固醇稳态的关键参与者低密度脂蛋白 (LDL) 受体 (LDLR) 是否受外源 H _{2 S 通过 LXRα 信号传导的调节。}我们研究了在 HepG2 细胞中存在或不存在 LXR 激动剂、T0901317 或 GW3965 时硫氢化钠（NaHS、H ₂ S 供体）对 LDLR 表达的影响。我们发现H ₂ S 在T0901317 存在下强烈积累LDLR 前体。因此，研究了 LDLR 转录和参与 LDLR 前体成熟和降解的基因。T0901317 增加了 LDLR mRNA 水平，而 H ₂S 不影响 LDLR 转录。H ₂ S对LXRα和LDLR诱导降解物(IDOL)的表达没有显着影响。H ₂ S 和 T0901317 改变了几种酶的 mRNA 水平，用于 N-和 O-糖基化和内质网 (ER) 伴侣，帮助 LDLR 成熟，但不影响它们的蛋白质水平。H ₂ S 降低了前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 蛋白水平，并且其 mRNA 水平因 T0901317 升高。T0901317 与 PCSK9 siRNA 也积累 LDLR 前体，T0901317 与 H _{2 S 也是如此。高葡萄糖增加 PCSK9 蛋白水平并减弱 T0901317 与 H 2} S诱导的 LDLR 前体积累。总之，H ₂S 通过下调 PCSK9 表达而不是通过 LXRα-IDOL 途径、LDLR 转录激活或糖基化酶和 ER 伴侣的功能障碍来积累 LDLR 前体。这些结果还表明，除了众所周知的对 LDLR 成熟形式降解的影响外，PCSK9 在 LDLR 成熟中也起重要作用。