Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA.
Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA; Department of Nutrition, the University of North Carolina at Greensboro, Greensboro, NC, USA.
Metabolism. 2023 Jan;138:155334. doi: 10.1016/j.metabol.2022.155334. Epub 2022 Oct 28.
Alcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty acids to lipid metabolic pathways. However, it remains unclear how ACSL1 contributes to the development of alcohol-associated liver disease (ALD).
We performed chronic alcohol feeding animal studies with hepatocyte-specific ACSL1 knockout (ACSL1) mice, hepatocyte-specific STAT5 knockout (STAT5) mice, and ACSL1 based-STAT5B overexpression (Stat5b-OE) mice. Cell studies were conducted to define the causal role of ACSL1 deficiency in the pathogenesis of alcohol-induced liver injury. The clinical relevance of the STAT5-ACSL1 pathway was examined using liver tissues from patients with alcoholic hepatitis (AH) and normal subjects (Normal).
We found that chronic alcohol consumption reduced hepatic ACSL1 expression in AH patients and ALD mice. Hepatocyte-specific ACSL1 deletion exacerbated alcohol-induced liver injury by increasing free fatty acids (FFA) accumulation and cell death. Cell studies revealed that FFA elicited the translocation of BAX and p-MLKL to the lysosomal membrane, resulting in lysosomal membrane permeabilization (LMP) and thereby initiating lysosomal-mediated cell death pathway. Furthermore, we identified that the signal transducer and activator of transcription 5 (STAT5) is a novel transcriptional regulator of ACSL1. Deletion of STAT5 exacerbated alcohol-induced liver injury in association with downregulation of ACSL1, and reactivation of ACSL1 by STAT5 overexpression effectively ameliorated alcohol-induced liver injury. In addition, ACSL1 expression was positively correlated with STAT5 and negatively correlated with cell death was also validated in the liver of AH patients.
ACSL1 deficiency due to STAT5 inactivation critically mediates alcohol-induced lipotoxicity and cell death in the development of ALD. These findings provide insights into alcohol-induced liver injury.
已有研究表明，饮酒会破坏肝脏脂质稳态。长链酰基辅酶 A 合成酶 1（ACSL1）通过将脂肪酸输送到脂质代谢途径，对肝脏脂肪酸代谢和脂质稳态起关键调控作用。然而，ACSL1 如何促进酒精相关性肝病（ALD）的发展仍不清楚。
我们通过肝实质细胞特异性 ACSL1 敲除（ACSL1）小鼠、肝实质细胞特异性 STAT5 敲除（STAT5）小鼠和 ACSL1 过表达（Stat5b-OE）小鼠进行了慢性酒精喂养动物研究。通过细胞研究来明确 ACSL1 缺乏在酒精性肝损伤发病机制中的因果作用。使用酒精性肝炎（AH）患者和正常对照者（Normal）的肝组织，研究了 STAT5-ACSL1 通路的临床相关性。
我们发现慢性酒精摄入降低了 AH 患者和 ALD 小鼠肝脏中的 ACSL1 表达。肝实质细胞特异性 ACSL1 缺失通过增加游离脂肪酸（FFA）积聚和细胞死亡加剧了酒精引起的肝损伤。细胞研究显示，FFA 诱导 BAX 和 p-MLKL 向溶酶体膜易位，导致溶酶体膜通透性（LMP），从而启动溶酶体介导的细胞死亡途径。此外，我们发现信号转导和转录激活因子 5（STAT5）是 ACSL1 的一种新型转录调节因子。STAT5 缺失加剧了酒精引起的肝损伤，同时下调了 ACSL1，而通过 STAT5 过表达重新激活 ACSL1 可有效改善酒精引起的肝损伤。此外，在 AH 患者的肝组织中还验证了 ACSL1 表达与 STAT5 呈正相关，与细胞死亡呈负相关。
由于 STAT5 失活导致的 ACSL1 缺失在 ALD 的发展过程中，对酒精诱导的脂肪毒性和细胞死亡起关键介导作用。这些发现为酒精性肝损伤提供了新的见解。
