CD38 Deficiency Protects Mice from High Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Activating NAD(+)/Sirtuins Signaling Pathways-Mediated Inhibition of Lipid Accumulation and Oxidative Stress in Hepatocytes.
CD38 Deficiency Protects Mice from High Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Activating NAD(+)/Sirtuins Signaling Pathways-Mediated Inhibition of Lipid Accumulation and Oxidative Stress in Hepatocytes.
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CD38 缺陷通过激活 NAD( )/Sirtuins 信号通路介导的肝细胞脂质积累和氧化应激抑制来保护小鼠免受高脂肪饮食诱导的非酒精性脂肪肝病
DOI：
10.7150/ijbs.65588
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发表时间：
2021
影响因子：
9.2
通讯作者：
Xin HB
中科院分区：
文献类型：
--
作者：
Xie L;Wen K;Li Q;Huang CC;Zhao JL;Zhao QH;Xiao YF;Guan XH;Qian YS;Gan L;Wang LF;Deng KY;Xin HB
非酒精性脂肪性肝病（NAFLD）的特点是肝细胞内脂质过度积聚。CD38最初被鉴定为淋巴细胞表面抗原，后来被发现存在于多种细胞类型中。我们之前的研究表明，CD38-/-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，我们报道了CD38-/-小鼠显著减轻了hfd诱导的肝脂肪变性。在体外和体内实验中，HFD或油酸显著提高小鼠肝组织和原代肝细胞或肝细胞系中CD38 mRNA和蛋白的表达，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缺乏分别显著降低HFD-或oa诱导的CD38-/-肝脏或原代肝细胞的脂质积累和氧化应激。相反，Hep1-6细胞中CD38的过度表达加重了oa诱导的脂质积累和氧化应激。此外，CD38缺乏显著抑制HFD-或oa诱导的NOX4的表达，增加CD38-/-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aa诱导的CD38-/-原代肝细胞的脂质积累和氧化应激，提示CD38缺乏的抗脂质积累可能依赖于NAD/ sirtuin介导的肝细胞中FAA β-氧化的增强和氧化应激的抑制。总之，我们证明了CD38缺乏通过激活NAD/Sirtuins信号通路减少脂质积累和抑制氧化应激来保护小鼠免受hfd诱导的NAFLD。
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 in vitro and in vivo, 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.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
64.8
作者：
Rodgers, JT;Lerin, C;Puigserver, P
通讯作者：
Puigserver, P
影响因子：
6
作者：
Gao, Qian;Jia, Yuzhi;Reddy, Janardan K.
通讯作者：
Reddy, Janardan K.
影响因子：
24.5
作者：
Montagner A;Polizzi A;Fouché E;Ducheix S;Lippi Y;Lasserre F;Barquissau V;Régnier M;Lukowicz C;Benhamed F;Iroz A;Bertrand-Michel J;Al Saati T;Cano P;Mselli-Lakhal L;Mithieux G;Rajas F;Lagarrigue S;Pineau T;Loiseau N;Postic C;Langin D;Wahli W;Guillou H
通讯作者：
Guillou H
影响因子：
13.8
作者：
Chini EN;Chini CCS;Espindola Netto JM;de Oliveira GC;van Schooten W
通讯作者：
van Schooten W