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

作者：Lin Xie, Ke Wen, Qian Li, Cong‐Cong Huang, Jiale Zhao, Qi‐Hang Zhao, Yun‐Fei Xiao, Xiao‐Hui Guan, Yisong Qian, Lu Gan, Lingfang Wang, Ke‐Yu Deng, Hong‐Bo Xin · 发表于：International Journal of Biological Sciences · 年份：2021 · DOI：10.7150/ijbs.65588 · 被引用次数：37 · 研究领域：Calcium signaling and nucleotide metabolism、Sirtuins and Resveratrol in Medicine、Lipid Membrane Structure and Behavior

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 PPAR, 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...