Cabré Noemí, Luciano-Mateo Fedra, Chapski Douglas J, Baiges-Gaya Gerard, Fernández-Arroyo Salvador, Hernández-Aguilera Anna, Castañé Helena, Rodríguez-Tomàs Elisabet, París Marta, Sabench Fàtima, Del Castillo Daniel, Del Bas Josep M, Tomé Mercedes, Bodineau Clément, Sola-García Alejandro, López-Miranda José, Martín-Montalvo Alejandro, Durán Raúl V, Vondriska Thomas M, Rosa-Garrido Manuel, Camps Jordi, Menéndez Javier A, Joven Jorge
Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain.
Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, US.
J Hepatol. 2021 May 4. doi: 10.1016/j.jhep.2021.04.037.
BACKGROUND & AIMS: A holistic insight on the relationship between obesity and metabolic dysfunction-associated fatty liver disease is an unmet clinical need. Omics investigations can be used to investigate the multifaceted role of altered mitochondrial pathways to promote nonalcoholic steatohepatitis, a major risk factor for liver disease-associated death. There are no specific treatments but remission via surgery might offer an opportunity to examine the signaling processes that govern the complex spectrum of chronic liver diseases observed in extreme obesity. We aim to assess the emerging relationship between metabolism, methylation and liver disease.
We tailed the flow of information, before and after steatohepatitis remission, from biochemical, histological, and multi-omics analyses in liver biopsies from patients with extreme obesity and successful bariatric surgery. Functional studies were performed in HepG2 cells and primary hepatocytes.
The reversal of hepatic mitochondrial dysfunction and the control of oxidative stress and inflammatory responses revealed the regulatory role of mitogen-activated protein kinases. The reversible metabolic rearrangements leading to steatohepatitis increased the glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy. The signaling activity of α-ketoglutarate and the associated metabolites also affected methylation-related epigenomic remodeling enzymes. Integrative analysis of hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis.
We provide evidence supporting the multifaceted potential of the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation as a conceivable source of the inefficient adaptive responses leading to steatohepatitis.
Steatohepatitis is a frequent and threatening complication of extreme obesity without specific treatment. Omics technologies can be used to identify therapeutic targets. We highlight increased glutaminolysis-induced α-ketoglutarate production as a potential source of signals promoting and exacerbating steatohepatitis.
全面了解肥胖与代谢功能障碍相关脂肪性肝病之间的关系是一项尚未满足的临床需求。组学研究可用于探究线粒体途径改变在促进非酒精性脂肪性肝炎（一种与肝病相关死亡的主要危险因素）中所起的多方面作用。目前尚无特效治疗方法，但通过手术实现病情缓解可能提供一个机会，来研究在极度肥胖中观察到的慢性肝病复杂谱所涉及的信号传导过程。我们旨在评估代谢、甲基化与肝病之间新出现的关系。
我们追踪了极度肥胖且接受成功减肥手术的患者肝活检中，在脂肪性肝炎缓解前后，来自生化、组织学和多组学分析的信息流。在HepG2细胞和原代肝细胞中进行了功能研究。
肝线粒体功能障碍的逆转以及氧化应激和炎症反应的控制揭示了丝裂原活化蛋白激酶的调节作用。导致脂肪性肝炎的可逆性代谢重排增加了谷氨酰胺分解诱导的α-酮戊二酸生成以及雷帕霉素靶蛋白复合物1的过度激活。这些变化对于通过协调细胞凋亡和自噬来调节肝细胞存活的腺苷单磷酸活化蛋白激酶/雷帕霉素靶蛋白驱动的途径至关重要。α-酮戊二酸及其相关代谢物的信号活性也影响了与甲基化相关的表观基因组重塑酶。对肝转录组特征和差异甲基化基因组区域的综合分析区分了有和没有脂肪性肝炎的患者。
我们提供的证据支持，谷氨酰胺分解增加诱导的α-酮戊二酸生成以及雷帕霉素靶蛋白复合物1失调具有多方面的潜在影响，这可能是导致脂肪性肝炎的低效适应性反应的一个可能来源。
脂肪性肝炎是极度肥胖常见且具有威胁性的并发症，目前尚无特效治疗方法。组学技术可用于识别治疗靶点。我们强调谷氨酰胺分解增加诱导的α-酮戊二酸生成是促进和加剧脂肪性肝炎的潜在信号来源。
