Das Sukanta, Subramaniyam Nithyananthan, Alén Rosa, Komakula Sai Santosh Babu, Song Zhuolun, Ge Xiaodong, Han Hui, Desert Romain, Athavale Dipti, Magdaleno Fernando, Chen Wei, Barahona Ines, Lantvit Daniel, Guzman Grace, Nieto Natalia
Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
Alcohol Clin Exp Res (Hoboken). 2024 May;48(5):781-794. doi: 10.1111/acer.15304. Epub 2024 Mar 19.
Previously, we demonstrated that Spp1 mice exhibit a greater susceptibility to alcohol-induced liver injury than wild-type (WT) mice. Notably, alcohol triggers the expression of osteopontin (encoded by SPP1) in hepatocytes. However, the specific role of hepatocyte-derived SPP1 in either mitigating or exacerbating alcohol-associated liver disease (AALD) has yet to be elucidated. We hypothesized that hepatocyte-derived SPP1 plays a role in AALD by modulating the regulation of steatosis.
We analyzed hepatic SPP1 expression using four publicly available datasets from patients with alcoholic hepatitis (AH). Additionally, we examined SPP1 expression in the livers of WT mice subjected to either a control or ethanol Lieber-DeCarli (LDC) diet for 6 weeks. We compared the relationship between SPP1 expression and significantly dysregulated genes in AH with controls using correlation and enrichment analyses. To investigate the specific impact of hepatocyte-derived SPP1, we generated hepatocyte-specific Spp1 knock-out (Spp1) mice and subjected them to either a control or ethanol Lieber-DeCarli diet for 6 weeks.
Alcohol induced hepatic SPP1 expression in both humans and mice. Our analysis, focusing on genes correlated with SPP1, revealed an enrichment of fatty acid oxidation (FAO) in three datasets, and peroxisome proliferator-activated receptor signaling in one dataset. Notably, FAO genes correlating with SPP1 were downregulated in patients with AH. Ethanol-fed WT mice exhibited higher serum-free fatty acids (FFAs), adipose tissue lipolysis, and hepatic fatty acid (FA) transporters. In contrast, ethanol-fed Spp1 mice displayed lower liver triglycerides, FFAs, and serum alanine transaminase and greater FAO gene expression than WT mice, indicating a protective effect against AALD. Primary hepatocytes from Spp1 mice exhibited heightened expression of genes encoding proteins involved in FAO.
Alcohol induces the expression of SPP1 in hepatocytes, leading to impaired FAO and contributing to the development of AALD.
此前，我们证明Spp1小鼠比野生型（WT）小鼠对酒精性肝损伤更敏感。值得注意的是，酒精会触发肝细胞中骨桥蛋白（由SPP1编码）的表达。然而，肝细胞衍生的SPP1在减轻或加重酒精相关性肝病（AALD）中的具体作用尚未阐明。我们假设肝细胞衍生的SPP1通过调节脂肪变性的调控在AALD中发挥作用。
我们使用来自酒精性肝炎（AH）患者的四个公开可用数据集分析肝脏SPP1表达。此外，我们检查了接受对照或乙醇利伯 - 德卡利（LDC）饮食6周的WT小鼠肝脏中的SPP1表达。我们使用相关性和富集分析比较了AH中SPP1表达与对照中显著失调基因之间的关系。为了研究肝细胞衍生的SPP1的具体影响，我们生成了肝细胞特异性Spp1基因敲除（Spp1）小鼠，并让它们接受对照或乙醇利伯 - 德卡利饮食6周。
酒精在人和小鼠中均诱导肝脏SPP1表达。我们对与SPP1相关基因的分析显示，在三个数据集中脂肪酸氧化（FAO）富集，在一个数据集中过氧化物酶体增殖物激活受体信号通路富集。值得注意的是，与SPP1相关的FAO基因在AH患者中下调。喂食乙醇的WT小鼠表现出更高的血清游离脂肪酸（FFA）、脂肪组织脂解和肝脏脂肪酸（FA）转运蛋白。相比之下，喂食乙醇的Spp1小鼠比WT小鼠表现出更低的肝脏甘油三酯、FFA和血清丙氨酸转氨酶以及更高的FAO基因表达，表明对AALD有保护作用。来自Spp1小鼠的原代肝细胞表现出参与FAO的蛋白质编码基因的表达增加。
酒精诱导肝细胞中SPP1的表达，导致FAO受损并促进AALD的发展。
