Mercer Kelly E, Pulliam Casey F, Pedersen Kim B, Hennings Leah, Ronis Martin Jj
1 Department of Pediatrics at the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
2 Arkansas Children's Nutrition Center, Little Rock, AR 72202, USA.
Exp Biol Med (Maywood). 2017 Mar;242(6):635-644. doi: 10.1177/1535370216685436. Epub 2017 Jan 5.
Alcoholic and nonalcoholic fatty liver diseases are risk factors for development of hepatocellular carcinoma, but the underlying mechanisms are poorly understood. On the other hand, ingestion of soy-containing diets may oppose the development of certain cancers. We previously reported that replacing casein with a soy protein isolate reduced tumor promotion in the livers of mice with alcoholic liver disease after feeding a high fat ethanol liquid diet following initiation with diethylnitrosamine. Feeding soy protein isolate inhibited processes that may contribute to tumor promotion including inflammation, sphingolipid signaling, and Wnt/β-catenin signaling. We have extended these studies to characterize liver tumor promotion in a model of nonalcoholic fatty liver disease produced by chronic feeding of high-fat liquid diets in the absence of ethanol. Mice treated with diethylnitrosamine on postnatal day 14 were fed a high-fat liquid diet made with casein or SPI as the sole protein source for 16 weeks in adulthood. Relative to mice fed normal chow, a high fat/casein diet led to increased tumor promotion, hepatocyte proliferation, steatosis, and inflammation. Replacing casein with soy protein isolate counteracted these effects. The high fat diets also resulted in a general increase in transcripts for Wnt/β-catenin pathway components, which may be an important mechanism, whereby hepatic tumorigenesis is promoted. However, soy protein isolate did not block Wnt signaling in this nonalcoholic fatty liver disease model. We conclude that replacing casein with soy protein isolate blocks development of steatosis, inflammation, and tumor promotion in diethylnitrosamine-treated mice fed high fat diets. Impact statement The impact of dietary components on cancer is a topic of great interest for both the general public and the scientific community. Liver cancer is currently the second leading form of cancer deaths worldwide. Our study has addressed the effect of the protein source on hepatic tumor promotion in a mouse model reflecting aspects of non-alcoholic fatty liver disease (NAFLD). A high-fat liquid diet with casein as the protein source promotes hepatic injury and tumor promotion in diethylnitrosamine-treated mice. Replacing casein with a soy protein isolate led to a pronounced diminishment of tumor promotion and associated hepatic injury and inflammation. The study thus demonstrates that a dietary protein source can have beneficial, preventative effects on hepatic tumor promotion.
酒精性和非酒精性脂肪性肝病是肝细胞癌发生的危险因素，但其潜在机制尚不清楚。另一方面，摄入含大豆的饮食可能会抑制某些癌症的发生。我们之前报道，在用二乙基亚硝胺启动后，给患有酒精性肝病的小鼠喂食高脂肪乙醇液体饮食，用大豆分离蛋白替代酪蛋白可减少肝脏中的肿瘤促进作用。喂食大豆分离蛋白可抑制可能有助于肿瘤促进的过程，包括炎症、鞘脂信号传导和Wnt/β-连环蛋白信号传导。我们将这些研究扩展到在无乙醇条件下长期喂食高脂肪液体饮食所产生的非酒精性脂肪性肝病模型中，对肝脏肿瘤促进作用进行表征。出生后第14天用二乙基亚硝胺处理的小鼠在成年后16周内喂食以酪蛋白或大豆分离蛋白作为唯一蛋白质来源的高脂肪液体饮食。相对于喂食正常饲料的小鼠，高脂肪/酪蛋白饮食导致肿瘤促进、肝细胞增殖、脂肪变性和炎症增加。用大豆分离蛋白替代酪蛋白可抵消这些影响。高脂肪饮食还导致Wnt/β-连环蛋白信号通路成分的转录普遍增加，这可能是促进肝脏肿瘤发生的一个重要机制。然而，在这个非酒精性脂肪性肝病模型中，大豆分离蛋白并没有阻断Wnt信号传导。我们得出结论，在用二乙基亚硝胺处理并喂食高脂肪饮食的小鼠中，用大豆分离蛋白替代酪蛋白可阻止脂肪变性、炎症和肿瘤促进的发展。影响声明饮食成分对癌症的影响是普通公众和科学界都非常感兴趣的话题。肝癌目前是全球第二大癌症死亡形式。我们的研究探讨了蛋白质来源对反映非酒精性脂肪性肝病（NAFLD）某些方面的小鼠模型中肝脏肿瘤促进作用的影响。以酪蛋白为蛋白质来源的高脂肪液体饮食会促进二乙基亚硝胺处理的小鼠的肝损伤和肿瘤促进作用。用大豆分离蛋白替代酪蛋白可显著减少肿瘤促进作用以及相关的肝损伤和炎症。因此，该研究表明饮食蛋白质来源对肝脏肿瘤促进作用可产生有益的预防效果。
