高胆固醇血症通常与肥胖症相关联，后者被视为各类癌症的危险因素。随着高胆固醇血症个体数量的增加，了解循环胆固醇或膳食胆固醇摄入增加对癌症病因学和病理学的作用变得必要。最近有报道称结肠癌患者血液胆固醇水平异常。在本研究中，我们证明胆固醇水平的改变（通过高胆固醇或高脂肪饮食）增加了化学致癌剂诱导的小鼠结肠息肉的发生率和肿瘤进展。在细胞水平上，低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇（HDL-C）通过调节细胞葡萄糖和脂质代谢促进结肠癌细胞增殖。在机制上，LDL-C或HDL-C的补充促进细胞葡萄糖摄取和利用，从而使结肠癌细胞产生乳酸增多。此外，LDL-C或HDL-C上调了有氧糖酵解，增加了通过糖酵解产生的总ATP，并减少了通过氧化磷酸化产生的ATP。有趣的是，胆固醇可利用性对于支持细胞快速增殖的更出现糖酵解表型的代谢状态转变。另外，在添加LDL-C或HDL-C的细胞中观察到胆固醇摄取相关分子的表达变化以及脂质和胆固醇积累的增加。这些结果表明结肠癌细胞直接利用与LDL-C或HDL-C相关的胆固醇。此外，通过乳酸脱氢酶抑制剂（乳酸酶抑制剂）靶向葡萄糖代谢可以明显消除LDL-C或HDL-C引起的细胞增殖。总体而言，我们阐明了胆固醇在调节癌细胞的葡萄糖和脂质代谢中的关键作用，以及其对结肠癌发生的直接影响。© 2023，BioMed Central Ltd.，施普林格自然出版集团的一部分。

Hypercholesterolemia is often correlated with obesity which is considered a risk factor for various cancers. With the growing population of hypercholesterolemic individuals, there is a need to understand the role of increased circulatory cholesterol or dietary cholesterol intake towards cancer etiology and pathology. Recently, abnormality in the blood cholesterol level of colon cancer patients has been reported. In the present study, we demonstrate that alteration in cholesterol levels (through a high-cholesterol or high-fat diet) increases the incidence of chemical carcinogen-induced colon polyp occurrence and tumor progression in mice. At the cellular level, low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc) promote colon cancer cell proliferation by tuning the cellular glucose and lipid metabolism. Mechanistically, supplementation of LDLc or HDLc promotes cellular glucose uptake, and utilization, thereby, causing an increase in lactate production by colon cancer cells. Moreover, LDLc or HDLc upregulates aerobic glycolysis, causing an increase in total ATP production through glycolysis, and a decrease in ATP generation by OXPHOS. Interestingly, the shift in the metabolic status towards a more glycolytic phenotype upon the availability of cholesterol supports rapid cell proliferation. Additionally, an alteration in the expression of the molecules involved in cholesterol uptake along with the increase in lipid and cholesterol accumulation was observed in cells supplemented with LDLc or HDLc. These results indicate that colon cancer cells directly utilize the cholesterol associated with LDLc or HDLc. Moreover, targeting glucose metabolism through LDH inhibitor (oxamate) drastically abrogates the cellular proliferation induced by LDLc or HDLc. Collectively, we illustrate the vital role of cholesterol in regulating the cellular glucose and lipid metabolism of cancer cells and its direct effect on the colon tumorigenesis.© 2023. BioMed Central Ltd., part of Springer Nature.