在高碳水化合物低脂肪饮食条件下,肝脏硬脂酰-CoA去饱和酶-1缺乏症会诱发肝纤维化和肝细胞癌相关基因激活。

IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jayne-Norah Ntambi , Mugagga Kalyesubula , Dylan Cootway , Sarah A. Lewis , Yar Xin Phang , Zhaojin Liu , Lucas M. O'Neill , Lucas Lefers , Hailey Huff , Jacqueline Rose Miller , Veronica Pegkou Christofi , Ethan Anderson , Ahmed Aljohani , Francis Mutebi , Mainak Dutta , Andrew Patterson , James M. Ntambi
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引用次数: 0

摘要

硬脂酰-CoA去饱和酶-1(SCD1)是脂肪生成过程中的一种关键酶,它催化饱和脂肪酸合成单不饱和脂肪酸(MUFA)。然而,SCD1的缺失会促进肝脏炎症和内质网应激,这就提出了肝脏SCD1缺失是否会进一步促进肝脏损伤(包括纤维化)的问题。为了明确 SCD1 缺乏是否会导致肝脏纤维化、肝硬化和肝细胞癌(HCC),我们采用了体内 SCD1 缺乏的高碳水化合物低脂肪饮食小鼠和肝脏特异性小鼠模型以及体外建立的 AML12 小鼠细胞。脂质体分析表明,肝脏 SCD1 的缺失明显增加了肝脏脂质种类的饱和度,并导致肝纤维化。同样,SCD1的缺失促进了与肝纤维化、肝硬化和肝癌相关的肝脏基因表达。SCD1 基因缺失会增加已知在肝纤维化中增加的骨化蛋白和甲胎蛋白的循环水平,而甲胎蛋白通常被用作 HCC 患者的早期标志物和预后标志物。新生脂肪生成或饮食中补充油酸(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。虽然 SCD1 缺乏的小鼠对肥胖和脂肪肝有保护作用,但我们的研究结果表明,MUFA 的缺失会导致肝损伤,包括纤维化,从而为我们提供了在非骨质疏松条件下 MUFA 不足与导致纤维化、肝硬化和 HCC 的途径之间的新见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet

Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet

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.

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来源期刊
CiteScore
11.00
自引率
2.10%
发文量
109
审稿时长
53 days
期刊介绍: BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.
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