Targeting alkaline ceramidase 3 alleviates the severity of nonalcoholic steatohepatitis by reducing oxidative stress
Targeting alkaline ceramidase 3 alleviates the severity of nonalcoholic steatohepatitis by reducing oxidative stress
复制标题
靶向碱性神经酰胺酶 3 可通过减少氧化应激来减轻非酒精性脂肪性肝炎的严重程度。
DOI：
10.1038/s41419-019-2214-9
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发表时间：
2020-01-16
影响因子：
9
通讯作者：
Mao, Cungui
中科院分区：
文献类型：
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作者：
Wang, Kai;Li, Chuanjiang;Mao, Cungui
棕榈酸的过量与非酒精性脂肪性肝炎（NASH）中神经酰胺代谢的失调有关，并且神经酰胺是介导NASH中棕榈酸的脂毒性的重要生物活性脂质。然而，关于催化NASH中神经酰胺水解的神经酰胺酶的作用仍不清楚。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（ACER 3）在NASH患者的肝脏中上调。一致地，我们发现Acer 3 mRNA水平和其酶活性也在富含棕榈酸盐的西方饮食（PEWD）诱导的NASH小鼠肝脏中上调。此外，我们证明棕榈酸酯治疗也提高Acer 3 mRNA水平和其在小鼠原代肝细胞中的酶活性。为了研究Acer 3在NASH中的功能，给Acer 3缺失小鼠和它们的野生型同窝仔喂食PEWD以诱导NASH。在NASH小鼠肝脏中，发现Acer 3敲除可增加PEWD诱导的C-18：1-神经酰胺升高，并减轻早期炎症和纤维化，但不减轻脂肪变性。此外，Acer 3缺陷减弱了NASH肝脏中的肝细胞凋亡。研究发现Acer 3缺乏的这些保护作用与NASH肝脏中肝细胞氧化应激的抑制有关。体外研究进一步表明，在棕榈酸处理诱导的小鼠原代肝细胞和永生化人肝细胞中，ACER 3/Acer 3的缺失增加了C-18：1-神经酰胺，并抑制了细胞凋亡和氧化应激。这些结果表明，ACER 3通过介导棕榈酸诱导的氧化应激在NASH中发挥重要的病理作用。
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 C-18:1-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 C-18:1-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.