硬脂酰辅酶A去饱和酶-1 (SCD1) 是脂肪生成中的关键酶，它催化饱和脂肪酸合成单不饱和脂肪酸 (MUFA)，其消除可下调脂质合成，防止脂肪变性和肥胖。然而，SCD1 的缺失会促进肝脏炎症和内质网应激，这引发了一个问题：肝脏 SCD1 缺乏是否会促进进一步的肝脏损伤，包括纤维化。为了阐明 SCD1 缺陷是否会使肝脏容易发生纤维化、肝硬化和肝细胞癌 (HCC)，我们采用了体内 SCD1 缺陷的整体和肝脏特异性小鼠模型，饲喂高碳水化合物低脂肪饮食，并在体外建立了 AML12 小鼠细胞。脂质组学分析表明，肝脏 SCD1 的缺失显着增加了肝脏脂质种类的饱和度，并导致肝纤维化。一致地，SCD1 缺陷促进了与纤维化、肝硬化和 HCC 相关的肝脏基因表达。 SCD1 的缺失增加了骨桥蛋白和甲胎蛋白的循环水平，骨桥蛋白会导致纤维化增加，甲胎蛋白通常用作 HCC 患者的早期标记物和预后标记物。从头脂肪生成或饮食补充油酸（一种 SCD1 生成的 MUFA）可恢复与纤维化、肝硬化和 HCC 相关的基因表达。尽管 SCD1 缺陷小鼠可以免受肥胖和脂肪肝的影响，但我们的结果表明，MUFA 剥夺会导致肝损伤，包括纤维化，从而提供了关于 MUFA 不足与瘦非脂肪性条件下导致纤维化、肝硬化和 HCC 的途径之间的新见解。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.Copyright © 2024 Elsevier B.V. All rights reserved.