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Abstract：
OBJECTIVE: Depression is associated with metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms underlying the interaction between them are still poorly known.
METHODS: In this study, mice on a choline deficiency, L-amino acid-defined, high-fat diet (CDAHFD) developing steatosis were challenged with chronic restraint stress (CRS), a protocol widely used to induce depression. The development of depression and steatosis was evaluated using histopathology analysis, ELISA, q-PCR and Western Blot.
RESULTS: The contribution of the activated HPA axis to hepatic steatosis progress was fully established, which was validated using a hepatocyte model. Histopathological and biochemical analysis indicated that steatosis was exacerbated by CRS challenge, and behavioral tests indicated that the mice developed depression. Among the screened endocrinal pathways, the hypothalamic-pituitary-adrenal (HPA) axis was significantly activated and the synergistic effect of CDAHFD and CRS in activating the HPA axis was observed. In the hypothalamus, expression of corticotropin-releasing hormone (CRH) was increased by 86% and the protein levels of hypothalamic CRH were upregulated by 25% to 33% by CRS treatment. Plasma CRH levels were elevated by 45-56% and plasma adrenocorticotropic hormone (ACTH) levels were elevated by 29-58% by CRS treatment. In the liver, target genes of the HPA axis were activated, accompanied by disruption of the lipid metabolism and progression of steatohepatitis. The lipid metabolism in the Hepa1-6 cell line treated with endogenous corticosterone (CORT) was in accordance with the aforementioned in vivo responses.
CONCLUSIONS: Depression aggravated hepatic steatosis in CDAHFD-fed mice by activating the HPA axis. The risk of NAFLD development should be fully considered in depressive patients and improvement of psychotic disorders could be an etiological treatment strategy for them.
METHODS: In this study, mice on a choline deficiency, L-amino acid-defined, high-fat diet (CDAHFD) developing steatosis were challenged with chronic restraint stress (CRS), a protocol widely used to induce depression. The development of depression and steatosis was evaluated using histopathology analysis, ELISA, q-PCR and Western Blot.
RESULTS: The contribution of the activated HPA axis to hepatic steatosis progress was fully established, which was validated using a hepatocyte model. Histopathological and biochemical analysis indicated that steatosis was exacerbated by CRS challenge, and behavioral tests indicated that the mice developed depression. Among the screened endocrinal pathways, the hypothalamic-pituitary-adrenal (HPA) axis was significantly activated and the synergistic effect of CDAHFD and CRS in activating the HPA axis was observed. In the hypothalamus, expression of corticotropin-releasing hormone (CRH) was increased by 86% and the protein levels of hypothalamic CRH were upregulated by 25% to 33% by CRS treatment. Plasma CRH levels were elevated by 45-56% and plasma adrenocorticotropic hormone (ACTH) levels were elevated by 29-58% by CRS treatment. In the liver, target genes of the HPA axis were activated, accompanied by disruption of the lipid metabolism and progression of steatohepatitis. The lipid metabolism in the Hepa1-6 cell line treated with endogenous corticosterone (CORT) was in accordance with the aforementioned in vivo responses.
CONCLUSIONS: Depression aggravated hepatic steatosis in CDAHFD-fed mice by activating the HPA axis. The risk of NAFLD development should be fully considered in depressive patients and improvement of psychotic disorders could be an etiological treatment strategy for them.
摘要：
目的：抑郁症与代谢紊乱有关，包括非酒精性脂肪性肝病（NAFLD）。然而,它们之间相互作用的潜在机制仍然知之甚少。
方法：在本研究中，小鼠胆碱缺乏，L-氨基酸定义，高脂饮食（CDAHFD）发展为脂肪变性受到慢性束缚应激（CRS）的挑战，广泛用于诱发抑郁症的方案。使用组织病理学分析评估抑郁症和脂肪变性的发展，ELISA,q-PCR和Western印迹。
结果：完全确定了活化的HPA轴对肝脂肪变性进展的贡献，使用肝细胞模型进行了验证。组织病理学和生化分析表明CRS攻击会加剧脂肪变性，行为测试表明老鼠患上了抑郁症。在筛选的内分泌途径中，下丘脑-垂体-肾上腺(HPA)轴被显著激活,观察到CDAHFD和CRS在激活HPA轴方面的协同作用.在下丘脑，通过CRS治疗,促肾上腺皮质激素释放激素(CRH)的表达增加了86%,下丘脑CRH的蛋白水平上调了25%~33%.通过CRS治疗，血浆CRH水平升高了45-56％，血浆促肾上腺皮质激素（ACTH）水平升高了29-58％。在肝脏中，HPA轴的靶基因被激活，伴随着脂质代谢的破坏和脂肪性肝炎的进展。用内源性皮质酮(CORT)处理的Hepa1-6细胞系中的脂质代谢与上述体内反应一致。
结论：抑郁通过激活HPA轴加重CDAHFD喂养小鼠的肝脂肪变性。抑郁症患者应充分考虑NAFLD发展的风险，改善精神障碍可能是他们的病因治疗策略。
方法：在本研究中，小鼠胆碱缺乏，L-氨基酸定义，高脂饮食（CDAHFD）发展为脂肪变性受到慢性束缚应激（CRS）的挑战，广泛用于诱发抑郁症的方案。使用组织病理学分析评估抑郁症和脂肪变性的发展，ELISA,q-PCR和Western印迹。
结果：完全确定了活化的HPA轴对肝脂肪变性进展的贡献，使用肝细胞模型进行了验证。组织病理学和生化分析表明CRS攻击会加剧脂肪变性，行为测试表明老鼠患上了抑郁症。在筛选的内分泌途径中，下丘脑-垂体-肾上腺(HPA)轴被显著激活,观察到CDAHFD和CRS在激活HPA轴方面的协同作用.在下丘脑，通过CRS治疗,促肾上腺皮质激素释放激素(CRH)的表达增加了86%,下丘脑CRH的蛋白水平上调了25%~33%.通过CRS治疗，血浆CRH水平升高了45-56％，血浆促肾上腺皮质激素（ACTH）水平升高了29-58％。在肝脏中，HPA轴的靶基因被激活，伴随着脂质代谢的破坏和脂肪性肝炎的进展。用内源性皮质酮(CORT)处理的Hepa1-6细胞系中的脂质代谢与上述体内反应一致。
结论：抑郁通过激活HPA轴加重CDAHFD喂养小鼠的肝脂肪变性。抑郁症患者应充分考虑NAFLD发展的风险，改善精神障碍可能是他们的病因治疗策略。
