Shanghai Renji Hospital, Jiaotong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China.
J Lipid Res. 2010 Jul;51(7):1696-703. doi: 10.1194/jlr.M003004. Epub 2010 Feb 24.
Dietary fatty acids are major contributors to the development and progression of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Dietary fatty acids also alter hepatic NKT cells that are activated by antigens presented by CD1d. In the current study, we examine the mechanism of dietary fatty acid induced hepatic NKT cell deficiency and its causal relationship to insulin resistance and NAFLD. We discover that dietary saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA), but not polyunsaturated fatty acids (PUFA), cause hepatic NKT cell depletion with increased apoptosis. Dietary SFA or MUFA also impair hepatocyte presentation of endogenous, but not exogenous, antigen to NKT cells, indicating alterations of the endogenous antigen processing or presenting pathway. In vitro treatment of normal hepatocytes with fatty acids also demonstrates impaired ability of CD1d to present endogenous antigen by dietary fatty acids. Furthermore, dietary SFA and MUFA activate the NFkappaB signaling pathway and lead to insulin resistance and hepatic steatosis. In conclusion, both dietary SFA and MUFA alter endogenous antigen presentation to hepatic NKT cells and contribute to NKT cell depletion, leading to further activation of inflammatory signaling, insulin resistance, and hepatic steatosis.
膳食脂肪酸是导致胰岛素抵抗和非酒精性脂肪性肝病（NAFLD）发生和进展的主要因素。膳食脂肪酸还会改变肝脏 NKT 细胞，这些细胞被 CD1d 呈递的抗原激活。在本研究中，我们研究了膳食脂肪酸诱导的肝 NKT 细胞缺乏的机制及其与胰岛素抵抗和 NAFLD 的因果关系。我们发现，膳食饱和脂肪酸（SFA）或单不饱和脂肪酸（MUFA），而不是多不饱和脂肪酸（PUFA），导致肝 NKT 细胞耗竭伴凋亡增加。膳食 SFA 或 MUFA 还损害肝细胞对内源性而非外源性抗原向 NKT 细胞的呈递，表明内源性抗原加工或呈递途径发生改变。脂肪酸对正常肝细胞的体外处理也表明，膳食脂肪酸会损害 CD1d 呈现内源性抗原的能力。此外，膳食 SFA 和 MUFA 激活 NFkappaB 信号通路，导致胰岛素抵抗和肝脂肪变性。总之，膳食 SFA 和 MUFA 改变了内源性抗原向肝 NKT 细胞的呈递，并导致 NKT 细胞耗竭，进而进一步激活炎症信号、胰岛素抵抗和肝脂肪变性。
