Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (J.J., L.T.G.N., T.P.R., X.-B.Z.); Departments of Pharmaceutics (A.W.) and Pharmacology and Toxicology (G.L.G.), Ernst Mario School of Pharmacy, and Center of Excellence for Pharmaceutical Translational Research and Education (A.W., R.S.), Rutgers University, Piscataway, New Jersey; Center of Excellence for Metabolic and Bariatric Surgery, Robert Wood Johnson Barnabas University Hospital, New Brunswick, New Jersey (A.W.); and Department of General Surgery, University of Kansas Medical Center, Kansas City, Kansas (T.M.S.).
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (J.J., L.T.G.N., T.P.R., X.-B.Z.); Departments of Pharmaceutics (A.W.) and Pharmacology and Toxicology (G.L.G.), Ernst Mario School of Pharmacy, and Center of Excellence for Pharmaceutical Translational Research and Education (A.W., R.S.), Rutgers University, Piscataway, New Jersey; Center of Excellence for Metabolic and Bariatric Surgery, Robert Wood Johnson Barnabas University Hospital, New Brunswick, New Jersey (A.W.); and Department of General Surgery, University of Kansas Medical Center, Kansas City, Kansas (T.M.S.)
Drug Metab Dispos. 2024 Oct 16;52(11):1345-1355. doi: 10.1124/dmd.124.001873.
Hepatocyte nuclear factor 4 alpha antisense 1 () is a long noncoding RNA (lncRNA) gene physically located next to the transcription factor 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 four annotated alternative transcripts in the human genome browsers, and it is unclear which transcripts the small interfering RNAs or small hairpin RNAs used in the previous studies are silenced and which transcripts should be used as the target. In this study, four annotated and two newly identified transcripts were confirmed. These six 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.
肝细胞核因子 4α 反义 1() 是一个长链非编码 RNA (lncRNA) 基因，在人类基因组中物理位置紧邻转录因子基因。其转录产物已被报道能抑制肝细胞癌 (HCC) 的进展，并负调控细胞色素 P450s (CYPs) 的表达，包括 CYP1A2、2B6、2C9、2C19、2E1 和 3A4。通过改变 CYP 的表达，lncRNA HNF4A-AS1 也导致了药物性肝损伤的易感性。因此，HNF4A-AS1 lncRNA 是控制 HCC 和调节药物代谢的有前途的靶点。然而，在人类基因组浏览器中，HNF4A-AS1 有四个注释的替代转录本，目前尚不清楚之前研究中使用的小干扰 RNA 或小发夹 RNA 沉默的是哪些转录本，以及应该将哪些转录本作为靶标。在这项研究中，确认了四个注释和两个新鉴定的转录本。这六个转录本在不同的肝病情况下表现出不同的表达水平，包括代谢功能相关的脂肪性肝病、酒精性肝病和肥胖症。在人胚胎干细胞向成熟肝细胞样细胞、HepaRG 分化以及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。HNF4A-AS1 转录本的几种表达模式与这些情况高度相关。此外，一些 HNF4A-AS1 转录本在 HepaRG 成熟和利福平暴露过程中与 CYP3A4 也表现出很强的相关性。我们的研究结果为 HNF4A-AS1 转录本的特定作用提供了有价值的见解，为肝脏疾病和药物代谢的更有针对性的治疗策略铺平了道路。意义：本研究探讨了 HNF4A-AS1 的替代转录本，展示了它们在不同的生物学条件下，从各种肝病到肝细胞的生长和分化以及药物代谢，表达如何变化。这些知识对于理解同一 lncRNA 的不同转录本在不同的肝脏疾病和药物代谢情况下的独立作用至关重要。
