Biomedical and Life Sciences, Lancaster University, Lancaster LA4 1YW, UK.
School of Psychological Sciences, Bristol University, Bristol BS8 1QU, UK.
Nutrients. 2024 Aug 22;16(16):2805. doi: 10.3390/nu16162805.
Both maternal obesity and postnatal consumption of obesogenic diets contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). However, there is no consensus as to whether diets that are high in fat or carbohydrates/sugars differentially influence the development of HCC. Moreover, the long-term effects of prenatal HF exposure on HCC and whether this is influenced by postnatal diet has not yet been evaluated. C57BL/6 dams were fed either a low-fat, high-carbohydrate control (C) or low-carbohydrate, high-fat (HF) diet. At weaning, male and female offspring were fed the C or HF diet, generating four diet groups: C/C, C/HF, HF/C and HF/HF. Tissues were collected at 16 months of age and livers were assessed for MASLD and HCC. Glucose regulation and pancreatic morphology were also evaluated. Liver tissues were assessed for markers of glycolysis and fatty acid metabolism and validated using a human HCC bioinformatic database. Both C/HF and HF/HF mice developed obesity, hyperinsulinemia and a greater degree of MASLD than C/C and HF/C offspring. However, despite significant liver and pancreas pathology, C/HF mice had the lowest incidence of HCC while tumour burden was highest in HF/C male offspring. The molecular profile of HCC mouse samples suggested an upregulation of the pentose phosphate pathway and a downregulation of fatty acid synthesis and oxidation, which was largely validated in the human dataset. Both pre-weaning HF diet exposure and post-weaning consumption of a high-carbohydrate diet increased the risk of developing spontaneous HCC in aged mice. However, the influence of pre-weaning HF feeding on HCC development appeared to be stronger in the context of post-weaning obesity. As rates of maternal obesity continue to rise, this has implications for the future incidence of HCC and possible dietary manipulation of offspring carbohydrate intake to counteract this risk.
母体肥胖和产后摄入致肥胖饮食都会导致代谢功能障碍相关脂肪性肝病 (MASLD) 和肝细胞癌 (HCC) 的发生。然而，目前尚不清楚高脂肪或高碳水化合物/糖饮食是否会对 HCC 的发生产生不同的影响。此外，产前 HF 暴露对 HCC 的长期影响，以及这种影响是否受产后饮食的影响，尚未得到评估。C57BL/6 孕鼠分别喂食低脂肪、高碳水化合物对照 (C) 或低碳水化合物、高脂肪 (HF) 饮食。在断奶时，雄性和雌性后代分别喂食 C 或 HF 饮食，共生成 4 种饮食组：C/C、C/HF、HF/C 和 HF/HF。在 16 个月时收集组织，评估 MASLD 和 HCC。还评估了葡萄糖调节和胰腺形态。评估了肝脏组织中糖酵解和脂肪酸代谢的标志物，并使用人类 HCC 生物信息学数据库进行了验证。C/HF 和 HF/HF 组小鼠均出现肥胖、高胰岛素血症和更严重的 MASLD，而 C/C 和 HF/C 组后代的 MASLD 则较轻。然而，尽管肝脏和胰腺有明显的病理改变，C/HF 组小鼠的 HCC 发生率最低，而 HF/C 雄性后代的肿瘤负担最高。HCC 小鼠样本的分子谱表明戊糖磷酸途径上调，脂肪酸合成和氧化下调，在人类数据集也得到了很大程度的验证。HF 饮食暴露前和高脂肪饮食暴露后，均增加了老年小鼠自发性 HCC 的发病风险。然而，在肥胖的背景下，HF 喂养前对 HCC 发展的影响似乎更强。随着母体肥胖率的持续上升，这对未来 HCC 的发病率产生了影响，可能需要通过控制后代碳水化合物的摄入来改变饮食，以抵消这种风险。
