Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia.
Am J Physiol Gastrointest Liver Physiol. 2023 Dec 1;325(6):G508-G517. doi: 10.1152/ajpgi.00160.2023. Epub 2023 Oct 3.
High-fat (HF) diets (HFDs) and inflammation are risk factors for colon cancer; however, the underlying mechanisms remain to be fully elucidated. The transcriptional corepressor HDAC3 has recently emerged as a key regulator of intestinal epithelial responses to diet and inflammation with intestinal-specific deletion () in mice increasing fatty acid oxidation genes and the rate of fatty acid oxidation in enterocytes. mice are also predisposed to experimentally induced colitis; however, whether this is driven by the intestinal metabolic reprogramming and whether this predisposes these mice to intestinal tumorigenesis is unknown. Herein, we examined the effects of intestinal-specific deletion on colitis-associated intestinal tumorigenesis in mice fed a standard (STD) or HFD. mice were highly prone to experimentally induced colitis, which was further enhanced by an HFD. deletion also accelerated intestinal tumor development, specifically when fed an HFD and most notably in the small intestine where lipid absorption is maximal. Expression of proteins involved in fatty acid metabolism and oxidation (SCD1, EHHADH) were elevated in the small intestine of mice fed an HFD, and these mice displayed increased levels of lipid peroxidation, DNA damage, and apoptosis in their villi, as well as extensive expansion of the stem cell and progenitor cell compartment. These findings reveal a novel role for in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover. We reveal a novel role for the transcriptional corepressor in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover. We also identify a unique mouse model for investigating the complex interplay between diet, metabolic reprogramming, and tumor predisposition in the intestinal epithelium.
高脂肪（HF）饮食（HFD）和炎症是结肠癌的风险因素；然而，其潜在机制仍有待充分阐明。转录核心抑制因子 HDAC3 最近成为调节肠道上皮对饮食和炎症反应的关键调节因子，其在肠道特异性缺失（）的小鼠中增加脂肪酸氧化基因和肠细胞中脂肪酸氧化的速度。缺失的小鼠也容易发生实验性结肠炎；然而，这是否是由肠道代谢重编程驱动的，以及这是否使这些小鼠易发生肠道肿瘤形成尚不清楚。在此，我们研究了肠道特异性缺失对高脂饮食喂养的小鼠中结肠炎相关肠道肿瘤发生的影响。缺失的小鼠极易发生实验性结肠炎，而高脂饮食进一步加重了这种情况。缺失还加速了肠道肿瘤的发展，特别是在喂食 HFD 时，并且在小肠中最为明显，因为小肠是脂质吸收最大的部位。在喂食 HFD 的缺失的小鼠的小肠中，参与脂肪酸代谢和氧化的蛋白质（SCD1、EHHADH）的表达升高，这些小鼠的绒毛中脂质过氧化、DNA 损伤和细胞凋亡水平增加，以及干细胞和祖细胞区室的广泛扩张。这些发现揭示了 在抑制结肠炎和肠道肿瘤发生中的新作用，特别是在摄入 HFD 的情况下，并且揭示了 HFD 通过增加脂肪酸氧化、DNA 损伤和肠道上皮细胞更替来增加肠道肿瘤发生的潜在机制。我们揭示了转录核心抑制因子在抑制结肠炎和肠道肿瘤发生中的新作用，特别是在摄入 HFD 的情况下，并且揭示了 HFD 通过增加脂肪酸氧化、DNA 损伤和肠道上皮细胞更替来增加肠道肿瘤发生的潜在机制。我们还鉴定了一种独特的小鼠模型，用于研究饮食、代谢重编程和肠道上皮中肿瘤易感性之间的复杂相互作用。
