Background & Aims

The molecular mechanism underlying metabolic dysfunction-associated steatotic liver disease (MASLD) is elusive and whether non-coding RNAs can serve as biomarkers and therapeutic targets of MASLD is less defined.

Methods

Exon capture RNA sequencing analysis was used to identify read-through circRNAs (rt-circRNAs) in livers from three MASLD patients and three patients without MASLD. Hepatocyte-specific deletion or overexpression of rt-circRNA RCRIN were utilized to study MASLD pathogenesis.

Results

We identified 1126 rt-circRNAs in the liver tissues from MASLD patients. RCRIN was highly expressed in normal livers and was downregulated in MASLD livers. Rcrin deletion in hepatocytes caused lipid accumulation and MASLD development, while Rcrin overexpression suppressed the MASLD progression. Mechanistically, in normal hepatocytes, highly expressed RCRIN bound to RPL8 protein to recruit RNF2 for its degradation, reducing RPL8-contained ribosome numbers and lipid accumulation. In MASLD livers, lowerly expressed RCRIN released RPL8 protein to promote RPL8-contained ribosome numbers and lipid synthesis, leading to higher lipid accumulation and ER stress. We synthesized RCRIN and N-acetylgalactosamine (GalNAc)–Rpl8 siRNA to treat established MASLD in mice, both of which suppressed MASLD pathogenesis.

Conclusions

Our findings provide an in vivo function of rt-circRNA RCRIN, show its inhibitory effects in MASLD pathogenesis, indicating RCRIN and RPL8 may be therapeutic targets and candidate nucleic acid drugs for treating MASLD.

Impact and Implications

Our finds reveal a novel mechanism connecting a read-through circRNA RCRIN, ribosome heterogeneity and MASLD pathogenesis. In normal hepatocytes, RCRIN exerts its role by reducing liver lipid accumulation and ER stress through promotion of RPL8 degradation. In MASLD patients, lower RCRIN releases RPL8 to form RPL8-contained ribosomes to promote lipid accumulation and ER stress. RCRIN overexpression and RPL8 depletion dramatically suppresses MASLD development and progression. Our findings indicate that RCRIN and RPL8 might be potential therapeutic targets for treatment of MASLD patients.

中文翻译：

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通读环状 RNA RCRIN 抑制代谢功能障碍相关的脂肪性肝病

 背景和目标

代谢功能障碍相关脂肪性肝病 （MASLD） 的分子机制尚不清楚，非编码 RNA 是否可以作为 MASLD 的生物标志物和治疗靶点尚不清楚。

 方法

外显子捕获 RNA 测序分析用于鉴定 3 例 MASLD 患者和 3 例无 MASLD 患者肝脏中的通读 circRNA （rt-circRNAs）。肝细胞特异性缺失或过表达 rt-circRNA RCRIN 用于研究 MASLD 发病机制。

 结果

我们在 MASLD 患者的肝组织中鉴定了 1126 个 rt-circRNA。RCRIN 在正常肝脏中高表达，在 MASLD 肝脏中下调。肝细胞中 Rcrin 缺失导致脂质积累和 MASLD 发展，而 Rcrin 过表达抑制 MASLD 进展。从机制上讲，在正常肝细胞中，高度表达的 RCRIN 与 RPL8 蛋白结合以募集 RNF2 进行降解，从而减少 RPL8 包含的核糖体数量和脂质积累。在 MASLD 肝脏中，低表达的 RCRIN 释放 RPL8 蛋白以促进含有 RPL8 的核糖体数量和脂质合成，导致更高的脂质积累和 ER 应激。我们合成了 RCRIN 和 N-乙酰半乳糖胺 （GalNAc）-Rpl8 siRNA 来治疗小鼠中已建立的 MASLD，这两者都抑制了 MASLD 的发病机制。

 结论

我们的研究结果提供了 rt-circRNA RCRIN 的体内功能，显示了其在 MASLD 发病机制中的抑制作用，表明 RCRIN 和 RPL8 可能是治疗 MASLD 的治疗靶点和候选核酸药物。

 影响和影响

我们的研究结果揭示了一种将通读 circRNA RCRIN、核糖体异质性和 MASLD 发病机制联系起来的新机制。在正常肝细胞中，RCRIN 通过促进 RPL8 降解来减少肝脂质积累和 ER 应激，从而发挥作用。在 MASLD 患者中，较低的 RCRIN 释放 RPL8 形成含有 RPL8 的核糖体，以促进脂质积累和 ER 应激。RCRIN 过表达和 RPL8 耗竭显着抑制 MASLD 的发生和进展。我们的研究结果表明，RCRIN 和 RPL8 可能是治疗 MASLD 患者的潜在治疗靶点。