食品安全问题是全球最关注的问题之一，多种食品都很有可能受到真菌的污染。人类主要是通过霉变的食品而接触到真菌毒素。杂色曲霉素（Sterigmatocystin, STC）和桔青霉素（Citrinin, CTN）作为由青霉和曲霉产生的真菌毒素，可广泛共存于霉变的食品中。研究表明，STC具有潜在的肝毒性和致癌性，而CTN可以导致体外和体内的肝毒性。事实上，肝脏是真菌毒素和脂质代谢的主要代谢器官，STC和CTN都与肝毒性相关，然而，STC和CTN的细胞毒性和对脂质代谢的潜在影响仍需进一步研究。本文探究STC和CTN对人肝细胞HL-7702细胞毒性的影响，利用基于HPLC-MS的非靶向脂质组学探究STC和CTN对内源性脂质代谢物的影响，并进一步地探究STC和CTN如何影响肝细胞的脂质代谢。主要的研究内容和结果如下：

STC和CTN均剂量依赖性地降低细胞活力，和增加细胞内ROS水平。此外，

STC可以触发细胞周期相关基因（如，周期蛋白依赖性激酶2和周期蛋白依赖性激酶4（Cyclin-dependent kinase 2 and Cyclin-dependent kinase 4, CDK2和CDK4）以及细胞周期蛋白依赖性激酶抑制因子（Cyclin dependent kinase inhibitors, CKIs）中的p15INK4b、p16INK4a 、p21Cip1、p27Kip1和p57Kip2（简称p15、p16、p21、p27和 p57））的异常表达，而CTN则导致细胞周期（周期蛋白依赖性激酶1 （Cyclin-dependent kinase 1, CDK1）、p21和p27） 的异常表达。另外，STC和CTN均能时间依赖性地诱导细胞凋亡，并在细胞凋亡的基因水平上得到了验证（BCL2家族蛋白（BCL-2 family proteins, BCL2, Bax, BAK）、半胱天冬氨酸蛋白酶3（Caspase3） 和半胱天冬氨酸蛋白酶3（Caspase8））。

脂质组学的多元统计分析表明，STC和CTN处理后，细胞内脂质代谢物均发生了显著性的变化。STC处理后内源脂质代谢产物，如溶血卵磷脂（Lysophosphatidylcholine, LPC）、溶血磷脂酰乙醇胺（ Lysophosphatidylethanolamine, LPE）、溶血磷脂酰（Lysophosphatidylglycerol, LPG）、溶血磷脂酰肌醇（Lysophosphatidylinositol, LPI）、磷脂酸（Phosphatidic acid, PA）、神经酰胺（Ceramides, Cer）、葡糖鞘氨醇（Glucosylsphingosine, CerG2GNAc1）、葡糖鞘氨醇（Glucosylsphingosine, CerG2）、葡糖鞘氨醇（Glucosylsphingosine, CerG3）、胆甾醇酯（Cholesterol ester, ChE）和脂肪酸（Fatty acid, FA）含量降低，而甘油三酯（Triglyceride, TG）和酰基肉碱（Acyl carnitine, AcCa）含量升高；CTN处理后内源脂质代谢产物中LPC、磷脂酰肌醇（Phosphatidylinositol (4,5) bisphosphate, PIP2）、PA、CerG2、CerG2GNAc1和FA含量明显降低。此外，STC处理组中代表性的内源脂质代谢分子，如LPC (16:0)、LPC (16:1)、LPC (18:0)、LPC (18:1)、LPC (18:2)、LPE (16:0)和FA (20:4) 也显著性地下降，而TG (16:0/16:1/16:1) 和 TG (18:1/18:1/18:2)的表达量显著性升高； CTN组中的LPC (16:0)、LPC (16:1)、LPC (17:0)、LPC (18:0)、LPC (18:1)、LPC (18:2)和FA (20:4)也明显地下降。

此外，在基因水平上，STC和CTN均能降低FA合成基因的表达，包括长链酰基-辅酶A合成酶1（Long chain acyl-CoA synthetases1, ACSL1）、脂肪酸去饱和酶1（Fatty acid desaturase1, FADS1 ）、长链脂肪酸延长酶5（Long-chain fatty acid elongase 5, ELOVL5）、脂肪酸合酶（Fatty acid synthase, FASN）和固醇调控元件结合蛋白1c（Sterol regulatory element-binding proteins 1c, SREBP1c）。而STC还能增强FA降解相关基因的表达，包括过氧化物酶体增殖物激活受体α（Peroxisome proliferator-activated receptor alpha, PPARα）和肉碱棕榈酰转移酶1α（Carnitine palmitoyl transferase 1al

pha, CPT1α），从而降低细胞内FA含量。

综上所述，STC和CTN均能抑制细胞增殖，促进ROS积累，导致细胞周期积聚，诱导细胞凋亡。STC和CTN均导致细胞内脂质代谢的紊乱。STC和CTN都能引起细胞内LPC和FA含量的降低，包括脂质分子 LPC (16:0)、LPC (16:1)、LPC(18:0)、LPC(18:1)、LPC(18:2)和FA(20:4)含量的下降。此外，STC还能诱导细胞内LPE、Cer的降低和TC的升高，以及脂质分子LPE(16:0)的降低、TG (16:0/16:1/16:1) 和 TG (18:1/18:1/18:2)的增强；而CTN还能导致细胞内LPC (17:0)的降低。在基因水平上，STC能通过减弱FA的合成和增强FA的分解而降低细胞内FA的含量，而CTN则主要降低FA的合成而降低细胞内FA的含量。因此，本研究对内源性脂质代谢产物的研究为探究STC和CTN的细胞毒性和对脂质代谢的影响提供了新的见解，从而为进一步研究STC和CTN的细胞毒性和脂质代谢的作用机制奠定基础。

Food safety is one of the most concerned issues in the world, and many kinds of food are likely to be contaminated by fungi. Humans are exposed to mycotoxins mainly through moldy foods. Sterigmatocystin (STC) and Citrinin (CTN), as mycotoxins produced by Penicillium and Aspergillus, could coexist widely in mildewy foods. Studies had shown that STC have potential hepatotoxicity and carcinogenicity, while CTN could cause hepatotoxicity in vitro and in vivo. The liver is the main metabolic organ for mycotoxin and lipid metabolism, and both STC and CTN are associated with hepatotoxicity. However, the cytotoxicity of STC and CTN and their potential effects on lipid metabolism need further research. Therefore, the effects of STC and CTN on the cytotoxicity of human hepatocyte HL-7702 cells were explored, and the effects of STC and CTN on endogenous lipid metabolites were explored using HPLC-MS based untargeted lipidomics, how STC and CTN affect lipid metabolism of hepatocytes was further explored. The main research contents and results are as follows:

 STC and CTN all reduced cell viability in a dose-dependent manner, and increased intracellular ROS levels. Additionally, ST

C triggered the abnormal expression of cell cycle-related genes, including Cyclin-dependent kinase 2 and Cyclin-dependent kinase 4 (CDK2 and CDK4), and p15INK4b, p16INK4a, p21Cip1, p27Kip1 and p57Kip2 (p15, p16, p21, p27 and p57) of cyclin dependent kinase inhibitors (CKIs), while CTN caused the abnormal expression of cell cycle-related genes (Cyclin-dependent kinase 1 (CDK1), p21 and p27). In addition, STC and CTN all induced caused apoptosis in a time-dependent manner and have been verified at the levels of apoptosis-related genes (BCL-2 family proteins (BCL2, Bax and BAK), Caspase3 and Caspase8).

Multivariate statistical analysis of lipidomics showed that the endogenous lipid metabolites changed significantly after STC and CTN treatment. The contents of endogenous lipid metabolites  decreased , such as lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylglycerol (LPG), lysophosphatidylinositol (Lysophosphatidylinositol, LPI), Phosphatidic acid (PA), Ceramides (Cer), Glucosylsphingosine (CerG2GNAc1), Glucosylsphingosine (CerG2), Glucosylsphingosine (Glucosylsphingosine, CerG3), Cholesterol ester (ChE) and fatty acid (FA) , whereas the contents of triglyceride (TG) and acyl carnitine (AcCa) increased after STC administration. The contents of LPC, Phosphatidylinositol (4,5) bisphosphate (PIP2), PA, CerG2, CerG2, GNAc1 and FA were also significantly reduced after CTN treatment. As the representative endogenous lipid metabolism molecules, such as LPC (16:0), LPC (16:1), LPC (18:0), LPC (18:1), LPC (18:2), LPE (16:0) and FA (20:4) the contents of these decreased significantly after STC treatment, while TG (16:0/16:1/16:1) and TG (18:1/18:1/18:2) increased dramatically. And the contents of LPC (16:0), LPC (16:1), LPC (17:0), LPC (18:0), LPC (18:1), LPC (18:2) and FA (20:4) also dramatically dropped after CTN-treated groups.

In addition, STC and CTN all reduced the expression of synthesis of FA, including long chain acyl-CoA synthetases1 (ACSL1), fatty acid desaturase1 (FADS1), long-chain fatty acid elongase 5 (ELOVL5), fatty acid synthase (FASN), sterol regulatory element-binding proteins 1c (SREBP1c). STC also enhanced the degradation of FA (Peroxisome proliferator-activated receptor alpha, PPARα and Carnitine palmitoyl transferase 1alpha, CPT1α) at the genetic level to reduce the intracellular contents of FA.

In summary, STC and CTN all inhibited cell proliferation, promoted ROS accumulation, led to cell cycle accumulation, and induced cell apoptosis. Both STC and CTN disturbed intracellular lipid metabolism. STC and CTN caused the reduction of intracellular LPC and FA, and decreased the contents of LPC (16:0), LPC (16:1), LPC (18:0), LPC (18: 1), LPC (18:2) and FA (20:4). Moreover, STC induced the reducing concentration of intracellular LPE and Cer, and enhancement of intracellular TG, as well as the reduction of LPE (16:0), and the increase of TG (16:0/16:1/16:1) and TG (18:1/18:1/18:2), while CTN declined the contents of intracellular LPC (17:0). In addition, STC reduced the contents of FA by weakening FA synthesis and enhancing the FA degradation, while CTN by reducing the synthesis of FA in the genetic level. Therefore, the study of endogenous lipid metabolites in this study provides new insights for exploring the cytotoxicity of STC and CTN and their effects on lipid metabolism, which lay a foundation for further study on the mechanism of cytotoxicity and lipid metabolism of STC and C

TN.

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