Overload of palmitic acids is linked to the dysregulation of ceramide metabolism in nonalcoholic steatohepatitis (NASH), and ceramides are important bioactive lipids mediating the lipotoxicity of palmitic acid in NASH. However, much remains unclear about the role of ceramidases that catalyze the hydrolysis of ceramides in NASH. By analyzing the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, we found that alkaline ceramidase 3 (ACER3) is upregulated in livers of patients with NASH. Consistently, we found that Acer3 mRNA levels and its enzymatic activity were also upregulated in mouse livers with NASH induced by a palmitate-enriched Western diet (PEWD). Moreover, we demonstrated that palmitate treatment also elevated Acer3 mRNA levels and its enzymatic activity in mouse primary hepatocytes. In order to investigate the function of Acer3 in NASH, Acer3 null mice and their wild-type littermates were fed a PEWD to induce NASH. Knocking out Acer3 was found to augment PEWD-induced elevation of C18:1-ceramide and alleviate early inflammation and fibrosis but not steatosis in mouse livers with NASH. In addition, Acer3 deficiency attenuated hepatocyte apoptosis in livers with NASH. These protective effects of Acer3 deficiency were found to be associated with suppression of hepatocellular oxidative stress in NASH liver. In vitro studies further revealed that loss of ACER3/Acer3 increased C18:1-ceramide and inhibited apoptosis and oxidative stress in mouse primary hepatocytes and immortalized human hepatocytes induced by palmitic-acid treatment. These results suggest that ACER3 plays an important pathological role in NASH by mediating palmitic-acid-induced oxidative stress.

中文翻译：

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靶向碱性神经酰胺酶3可通过减少氧化应激缓解非酒精性脂肪性肝炎的严重程度。

棕榈酸的超载与非酒精性脂肪性肝炎（NASH）中神经酰胺代谢异常有关，神经酰胺是重要的生物活性脂质，介导NASH中棕榈酸的脂毒性。然而，关于陶瓷酶在NASH中催化神经酰胺水解的作用尚不清楚。通过分析美国国家生物技术信息中心（NCBI）基因表达综合数据库（GEO），我们发现碱性神经酰胺酶3（ACER3）在NASH患者肝脏中上调。一致地，我们发现在富含棕榈酸酯的西方饮食（PEWD）诱导的NASH小鼠肝脏中，Acer3 mRNA水平及其酶活性也被上调。此外，我们证明棕榈酸酯处理还提高了小鼠原代肝细胞中的Acer3 mRNA水平及其酶促活性。为了研究Acer3在NASH中的功能，给Acer3无效小鼠及其野生型同窝小鼠喂食PEWD以诱导NASH。发现敲除Acer3可增加PEWD诱导的NASH小鼠肝脏中CWD：1-神经酰胺的升高，并减轻早期炎症和纤维化，但不能减轻脂肪变性。此外，Acer3缺乏症减弱了NASH肝脏中肝细胞的凋亡。发现Acer3缺乏的这些保护作用与抑制NASH肝中的肝细胞氧化应激有关。体外研究进一步表明，ACER3 / Acer3的缺失会增加棕榈酸处理诱导的小鼠原代肝细胞和永生化人类肝细胞的C18：1-神经酰胺，并抑制细胞凋亡和氧化应激。