Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain.
Mol Metab. 2018 Feb;8:132-143. doi: 10.1016/j.molmet.2017.12.005. Epub 2017 Dec 15.
Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat) and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet). We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2).
The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability.
These data provide new evidence for targeting p53 as a strategy to treat liver disease.
最近的报告表明，p53 肿瘤抑制因子参与了脂代谢的调节。我们假设，用低剂量多柔比星（广泛用于治疗多种癌症）进行 p53 的药理学激活可能对非酒精性脂肪性肝病 (NAFLD) 和非酒精性脂肪性肝炎 (NASH) 有有益作用。
我们使用腹腔内或口服给予低剂量多柔比星来长期激活 p53，在不同的 NAFLD 动物模型（含 45%和 60%热量脂肪的高脂肪饮食）和 NASH 模型（蛋氨酸和胆碱缺乏饮食以及胆碱缺乏与高脂肪饮食联合）中进行。我们还在肝脏缺乏 p53 的小鼠以及两种人类肝细胞系（HepG2 和 THLE2）中给予多柔比星。
肝损伤的减轻伴随着脂肪酸氧化的刺激和脂肪生成、炎症和 ER 应激的减少。p53 在肝脏特异性缺失的小鼠中，多柔比星的作用被消除。最后，在动物模型中发现的多柔比星对脂质代谢的影响也存在于两种人类肝细胞系中，在这些细胞系中，药物在不引起细胞凋亡或细胞活力变化的剂量下刺激脂肪酸氧化并抑制从头脂肪生成。
这些数据为将 p53 作为治疗肝病的策略提供了新的证据。
