National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine.
School of Life Science, Nanchang University, Nanchang 330031, P.R. China.
Int J Biol Sci. 2021 Oct 17;17(15):4305-4315. doi: 10.7150/ijbs.65588. eCollection 2021.
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes. CD38 was initially identified as a lymphocyte surface antigen and then has been found to exist in a variety of cell types. Our previous studies showed that CD38 mice were resistant to high-fat diet (HFD)-induced obesity. However, the role and mechanism of CD38 in HFD-induced NAFLD is still unclear. Here, we reported that CD38 mice significantly alleviated HFD-induced hepatic steatosis. HFD or oleic acid (OA) remarkably increased the mRNA and protein expressions of CD38 in mouse hepatic tissues and primary hepatocytes or hepatic cell lines and , suggesting that CD38 might play a role in HFD-induced hepatic steatosis. We observed that CD38 deficiency markedly decreased HFD- or OA-induced the lipid accumulation and oxidative stress in CD38 livers or primary hepatocytes, respectively. In contrast, overexpression of CD38 in Hep1-6 cells aggravated OA-induced lipid accumulation and oxidative stress. Furthermore, CD38 deficiency markedly inhibited HFD- or OA-induced the expressions of NOX4, and increased the expression of PPARα, CPT1, ACOX1 and SOD2 in liver tissue and hepatocytes from CD38 mice, indicating that CD38 deficiency-mediated the enhancement of fatty acid oxidation and the inhibition of oxidative stress contributed to protecting NAFLD. More importantly, Ex527 (Sirt1 inhibitor) and 3-TYP (Sirt3 inhibitor) significantly enhanced OA-induced lipid accumulation and oxidative stress in CD38 primary hepatocytes, suggesting that the anti-lipid accumulation of CD38 deficiency might be dependent on NAD/Sirtuins-mediated enhancement of FAA β-oxidation and suppression of oxidative stress in hepatocytes. In conclusion, we demonstrated that CD38 deficiency protected mice from HFD-induced NAFLD by reducing lipid accumulation and suppressing oxidative stress via activating NAD/Sirtuins signaling pathways.
非酒精性脂肪性肝病（NAFLD）的特征是肝细胞内脂质蓄积过多。CD38 最初被鉴定为淋巴细胞表面抗原，后来发现它存在于多种细胞类型中。我们之前的研究表明，CD38 敲除小鼠对高脂肪饮食（HFD）诱导的肥胖具有抗性。然而，CD38 在 HFD 诱导的 NAFLD 中的作用和机制尚不清楚。在这里，我们报道 CD38 敲除小鼠显著减轻了 HFD 诱导的肝脂肪变性。HFD 或油酸（OA）显著增加了小鼠肝组织和原代肝细胞或肝细胞系中 CD38 的 mRNA 和蛋白表达，提示 CD38 可能在 HFD 诱导的肝脂肪变性中发挥作用。我们观察到 CD38 缺乏显著减少了 HFD 或 OA 诱导的 CD38 肝脏或原代肝细胞中的脂质蓄积和氧化应激，相反，在 Hep1-6 细胞中过表达 CD38 则加剧了 OA 诱导的脂质蓄积和氧化应激。此外，CD38 缺乏显著抑制了 HFD 或 OA 诱导的 NOX4 表达，并增加了 CD38 敲除小鼠肝组织和肝细胞中 PPARα、CPT1、ACOX1 和 SOD2 的表达，表明 CD38 缺乏介导的脂肪酸氧化增强和氧化应激抑制有助于保护 NAFLD。更重要的是，Ex527（Sirt1 抑制剂）和 3-TYP（Sirt3 抑制剂）显著增强了 CD38 原代肝细胞中 OA 诱导的脂质蓄积和氧化应激，表明 CD38 缺乏的抗脂质蓄积作用可能依赖于 NAD/Sirtuins 介导的增强的脂肪酸 β-氧化和抑制肝细胞中的氧化应激。总之，我们证明 CD38 缺乏通过激活 NAD/Sirtuins 信号通路减少脂质蓄积和抑制氧化应激来保护小鼠免受 HFD 诱导的 NAFLD。
