High-Refined-Carbohydrate and High-Fat Diets Induce Comparable Hepatic Tumorigenesis in Male Mice

Previous studies demonstrated that diet-induced obese mice fed a semi-purified high-fat diet (HFD) had greater liver tumorigenesis than mice fed a non-semi-purified diet. Because ingredients present in standard unpurified diets may elicit potential chemopreventive properties that are not present in semi-purified diets, the present study evaluated hepatic tumorigenic effects of dietary fat by replacing it with refined carbohydrates [digestible saccharides; high-carbohydrate diet (HOD)] in a semi-purified diet without altering other components. Two-wk-old C57BI/6J male mice were randomly injected i.p. with either the liver-specific carcinogen diethylnitrosamine (25 mg/kg body weight) to induce liver cancer or saline as the nontumor control. At ages wk, mice with or without cancer initiation were further randomly assigned to an HFD (26% and 60% energy from carbohydrates and fat, respectively) or an HOD (66% and 12% energy from carbohydrates and fat, respectively) and consumed food ad libitum for 24 wk. Results showed that HOD-fed mice had a comparable degree of hepatic tumorigenesis (tumor number and volume) as HFD-fed mice, despite having significantly reduced body weights. HOD feeding induced greater hepatic endoplasmic reticulum (ER) stress-mediated protein kinase RNA-activated-like kinase (PERK) activation and oncogenic interleukin-6/signal transducer and activator of transcription 3 signaling than HFD feeding. HOD-stimulated PERK signaling was associated with elevated expression of prosurvival markers in tumors, including induced protein kinase B activation, increased extracellular signal-regulated kinases 1/2 phosphorylation, and elevated cyclin D1 protein expression. However, HOD-mediated PERK activation in tumors was also positively associated with markers of proapoptosis, which included elevated CCAAT/enhancer-binding protein homology protein expression and increased cleaved caspase-3. HCD-fed mice had greater severity in hepatic steatosis than HFD-fed mice. HCD-induced steatosis exacerbation was associated with increased expression in hepatic de novo lipogenic markers that can promote ER stress. Together, these data indicated that chronic HOD consumption by mice can produce comparable severity of hepatic tumorigenesis as HFD consumption, potentially through upregulating PERK-mediated ER stress.