肥胖易患癌,动物实验 z-bo 2020-12-17 361

　　Obesity is a high risk factor for colorectal cancer. Recent animal experiment results suggest that the underlying basis of this association is that feeding animals with a high-fat diet can increase the number of stem cells in the intestine due to the activation of a protein related to metabolic regulation, PPAR-δ. After PPAR binds to the ligand and activates, it forms a heterodimer with the retinol X receptor (RXR). The formed PPAR/RXR heterodimer binds to the PPAR response element (PPRE) upstream of the target gene promoter, and finally Regulate the transcription of target genes. The ligand is a fat-soluble molecule. After the receptor binds to the ligand, the biological effect is mainly produced by regulating the expression of the target gene. The combination of PPARs with their respective ligands causes their own conformational changes and promotes or inhibits the expression of target genes. PPAR is the peroxisome proliferation activation receptor, a member of the nuclear receptor superfamily, and there are three subtypes in lower vertebrates and mammals, PPAR-α, PPAR-γ, and PPAR-δ. PPAR α is mainly expressed in brown adipose tissue, liver, kidney, duodenum, heart, skeletal muscle and vascular endothelial cells, and is related to the control of lipoprotein metabolism, fatty acid oxidation, and cell intake of fatty acids. PPAR γ is highly expressed in brown and white adipose tissue, and plays an important role in fat differentiation and fat accumulation. PPAR δ is widely distributed in tissues and plays an important role in lipid metabolism, inflammation, skin wound healing, keratinocyte differentiation and proliferation, and cancer formation. Human epidemiological studies have found that the incidence of colorectal cancer in overweight and obese people will increase. Although there is no similar evidence from human studies, this study provides a reasonable explanation for this epidemiological result and will promote it. Find relevant evidence in clinical research. The research leader, cancer biologist?mer Yilmaz of MIT's Koch Institute for Cancer Research, said that this research model will also promote the research of more tissue types and obesity-related cancers, and understand the underlying phenomena of cancer. The mechanism is of interest to scientists.

　　 University of North Carolina cell biologist P. Kay Lund believes that it is important to understand the molecular details behind these phenomena. In particular, colonoscopy should be used to collect living tissue from the patient's large intestine to verify whether this molecular change pattern is similar. If this is the case, then the PPAR-δ activity will be called an important tool to control and prevent the occurrence of colorectal cancer, and clinically, early preventive measures can be taken against colorectal cancer.

　　 Yilmaz collaborated with Professor David Sabatini, a colleague of MIT who studies metabolism, to conduct research on the relationship between obesity and cancer. They gave the mice a high-fat and high-calorie diet for one year, and then analyzed the changes in the number and function of stem cells in the intestine. A diet with a fat ratio of up to 60% not only allows mice to overeat and gain excessive weight, but also activates the PPAR-δ pathway and stimulates the division of intestinal stem cells. Treatment of mice with activating PPAR-δ drugs can produce similar cell proliferation effects. It is currently believed that stem cells are the main source of cells for tumors.

　　 It is still not known whether this change is caused by weight gain, and the metabolic change is caused by weight gain or the accompanying phenomenon of fat diet. The research team used three-dimensional cell culture, or micro-organ culture, to study the effect of fatty acids related to high-fat diet in stimulating intestinal cell proliferation. The PPAR-δ of these cells was also activated, suggesting that fatty acids may directly activate the expression of PPAR-δ.

　　 Harvard University public nutritionist Walter Willett believes that if it is really the direct stimulating effect of fatty acids, it logically cannot explain the internal relationship between human obesity and colorectal cancer. Because there is no very definite evidence between human cancer and fat diet, further research is needed. However, Yilmaz pointed out that there are many influencing factors in epidemiological investigation and research. The data on the relationship between fat diet and cancer is indeed confusing. Their team hopes to clarify the relationship between fatty acids and cancer, and will also study the results of high-fat diets in normal-weight mice.