Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

Abstract

Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine.

Obesity and Hepatocellular Carcinoma: A Complex Relationship

“…For example, high-sugar diets in diethylnitrosamine-treated mice were more tumorigenic than high-fat diets, irrespective of obesity or insulin resistance. 10 Similar findings were noted in another study, which showed that a combination high-sugar and high-fat diet in mice led to progressive NASH, as well as an increased risk of developing HCC. 11 Also seen were lower adiponectin levels, 10 which have been shown previously to have an inverse relationship to the development of HCC.…”

“…10 Similar findings were noted in another study, which showed that a combination high-sugar and high-fat diet in mice led to progressive NASH, as well as an increased risk of developing HCC. 11 Also seen were lower adiponectin levels, 10 which have been shown previously to have an inverse relationship to the development of HCC. 12 Similar findings of an inverse relationship with adiponectin levels have been associated with polymorphisms of the PNPLA3 gene.…”

Transgenic mouse models generated by hydrodynamic transfection for genetic studies of liver cancer and preclinical testing of anti‐cancer therapy

“…Malignant cells heavily rely on glucose for increased energy production and metabolic processes required for rapid cellular proliferation . Studies have shown that dietary carbohydrate restriction is a promising anti‐cancer therapy . To test a tumor prevention effect of dietary carbohydrate restriction in hepatocarcinogenesis, Lee et al .…”

“…103,104 Studies have shown that dietary carbohydrate restriction is a promising anti-cancer therapy. 105,106 To test a tumor prevention effect of dietary carbohydrate restriction in hepatocarcinogenesis, Lee et al used an HT model of HCC induced by an activated RAS and p53 suppression. Mice were fed an isocaloric carbohydrate-restriction diet beginning 2 weeks prior to hydrodynamic transfection and throughout the 6-week experiment.…”

Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival

“…Sample size sufficient to detect a 20% change in tumour number was estimated a priori , using a power analysis based on group means and s.d. 's previously reported2223. Offspring female LDKO and Flox mice were treated with 25 mg kg −1 DEN at 14 days of age via intraperitoneal injection.…”