肝细胞核因子 4 α 反义 1 (HNF4A-AS1) 是一种长非编码 RNA (lncRNA) 基因，在人类基因组中物理位置靠近转录因子 HNF4A 基因。据报道，其转录产物可抑制肝细胞癌 (HCC) 的进展，并负向调节细胞色素 P450 (CYP) 的表达，包括 CYP1A2、2B6、2C9、2C19、2E1 和 3A4。通过改变 CYP 表达，lncRNA HNF4A-AS1 也有助于药物引起的肝损伤的易感性。因此，HNF4A-AS1 lncRNA 是控制 HCC 和调节药物代谢的有希望的靶标。然而，HNF4A-AS1在人类基因组浏览器中有4个带注释的替代转录本，目前尚不清楚之前研究中使用的siRNA或shRNA中哪些转录本被沉默以及哪些转录本应作为靶标。在这项研究中，确认了 4 个带注释的转录本和 2 个新鉴定的转录本。这6个转录本在不同的肝脏疾病条件下表现出不同的表达水平，包括代谢功能障碍相关的脂肪肝病、酒精相关的肝病和肥胖。在从人胚胎干细胞到成熟肝细胞样细胞的肝细胞生长、HepaRG 分化和暴露于利福平治疗的过程中，进一步研究了所有 HNF4A-AS1 转录本的表达模式。一些 HNF4A-AS1 转录本与这些情况高度相关。此外，一些 HNF4A-AS1 转录本在 HepaRG 成熟和利福平暴露期间也显示出与 CYP3A4 的强相关性。我们的研究结果为了解 HNF4A-AS1 转录本的具体作用提供了宝贵的见解，为肝病和药物代谢更有针对性的治疗策略铺平了道路。意义声明 本研究探索了 HNF4A-AS1 的替代转录本，展示了它们的表达在不同的生物条件下（从各种肝脏疾病到肝细胞的生长和分化以及药物代谢）如何变化。生成的知识对于理解相同 lncRNA 的不同转录本在不同肝脏疾病和药物代谢情况下的独立作用至关重要。版权所有 © 2024 美国药理学和实验治疗学会。

Hepatocyte nuclear factor 4 alpha antisense 1 (HNF4A-AS1) is a long non-coding RNA (lncRNA) gene physically located next to the transcription factor HNF4A gene in the human genome. Its transcription products have been reported to inhibit the progression of hepatocellular carcinoma (HCC) and negatively regulate the expression of cytochrome P450s (CYPs), including CYP1A2, 2B6, 2C9, 2C19, 2E1, and 3A4. By altering CYP expression, lncRNA HNF4A-AS1 also contributes to the susceptibility of drug-induced liver injury. Thus, HNF4A-AS1 lncRNA is a promising target for controlling HCC and modulating drug metabolism. However, HNF4A-AS1 has 4 annotated alternative transcripts in the human genome browsers, and it is unclear which transcripts the siRNAs or shRNAs used in the previous studies are silenced and which transcripts should be used as the target. In this study, 4 annotated and 2 newly identified transcripts were confirmed. These 6 transcripts showed different expression levels in different liver disease conditions, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and obesity. The expression patterns of all HNF4A-AS1 transcripts were further investigated in liver cell growth from human embryonic stem cells to matured hepatocyte-like cells, HepaRG differentiation, and exposure to rifampicin treatment. Several HNF4A-AS1 transcripts highly displayed correlations with these situations. In addition, some of the HNF4A-AS1 transcripts also showed a strong correlation with CYP3A4 during HepaRG maturation and rifampicin exposure. Our findings provide valuable insights into the specific roles of HNF4A-AS1 transcripts, paving the way for more targeted therapeutic strategies for liver diseases and drug metabolism. Significance Statement This study explores the alternative transcripts of HNF4A-AS1, showing how their expression changes in different biological conditions, from various liver diseases to the growth and differentiation of hepatocytes, and drug metabolism. The generated knowledge is essential for understanding the independent roles of different transcripts from the same lncRNA in different liver diseases and drug metabolism situations.Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.