Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil

Abstract

Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial β-oxidation (CPT1α) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism.

Hepatocyte steatosis activates macrophage inflammatory response accelerating atherosclerosis development

“…网络药理学分析结果得到差异代谢产物影响动脉粥样硬化和NAFLD共病的11个关键基因，其中 PPARG 、 PPARA 、 PTPN1 、 SCD 与脂代谢密切相关， STAT3 、 NFKB1 、 PTGS2 与炎症密切相关。 PPARG 和 PPARA 是过氧化物酶体增殖物激活受体的一员，作为脂肪酸传感器，是多种人类脂质代谢疾病的治疗靶点，可通过与类视黄醇X受体结合形成PPAR-RXR异二聚体，调节脂肪酸氧化基因的转录，抑制炎症因子的表达，影响巨噬细胞胆固醇的转运，影响动脉粥样硬化 ［ 25 ］ 。 PTPN1 是PTP超家族的成员，研究发现用高脂肪饮食喂养的 PTP8B 敲除小鼠对体重增加具有抵抗力，并且三酰甘油水平显著降低，因此， PTP1B 是治疗脂代谢异常相关疾病的潜在靶点 ［ 26 - 27 ］ 。 PTPN1 还参与巨噬细胞极化，敲除 PTPN1 将巨噬细胞向抗炎M2表型转移，从而促进肠屏障完整性并抑制巨噬细胞的炎症反应 ［ 28 ］ 。 SCD 影响脂肪酸合成途径，在调节参与脂肪生成的基因的表达和调节线粒体脂肪酸氧化方面发挥重要作用，在NAFLD患者中可见 SCD 基因表达上调 ［ 29 ］ 。巨噬细胞是炎症细胞的重要组成部分，包括促炎M1型和抗炎M2型，M1型巨噬细胞的促炎反应依赖于 NFKB1 的激活；M2型巨噬细胞会通过募集 STAT3 抑制炎症 ［ 30 ］ 。 PTGS2 基因的重要功能之一是参与炎症反应的调节，其翻译的环氧合酶通过催化花生四烯酸代谢和前列腺素合成的初始步骤，是炎症的主要介质，可作为治疗炎症性疾病的治疗靶点 ［ 31 ］ 。KEGG通路富集分析结果得到的信号通路有PPAR信号通路、糖尿病并发症中的AGE-RAGE信号通路、酒精性肝病、胰岛素抵抗、TNF信号通路等，因此推测差异代谢物影响了共病模型中的脂代谢及炎症表型。…”