Dietary Tomato Powder Inhibits Hepatic Steatosis, Inflammation and Tumorigenesis in Beta‐carotene‐15, 15′‐oxygenase (BCO1) and Beta‐carotene‐9, 10′‐oxygenase (BCO2) Double Knockout Mice

Abstract

Consumption of tomatoes and tomato products which are rich in lycopene, is associated with a decreased risk of chronic disease. Lycopene can be cleaved by beta‐carotene‐15, 15′‐oxygenase (BCO1) and beta‐carotene‐9′, 10′‐oxygenase (BCO2) to produce biological active apolycopenoids. We have recently shown that lycopene and apolycopenoid have different mechanisms of protection against high fat diet (HFD)‐induced hepatic steatosis and hepatocellular carcinoma (HCC) development in BCO2 knockout (KO) mice (Ip, 2014, 2015). Since apolycopenoids also exist in tomato and tomato products (Kopec, 2010), the present investigation examined whether or not the whole tomato (tomato powder, TP) can inhibit HFD‐induced hepatic steatosis, inflammation and HCC in the absence of both BCO1/BCO2 in mice.BCO1/BCO2 double KO mice were injected with a carcinogen (diethylnitrosamine, i.p. 25 mg/kg body weight) at 2 weeks of age. At the age of 6 weeks, the mice were randomly assigned to either the HFD (n=9, 60% of energy as fat) feeding alone group or the HFD feeding with TP supplementation (n=9, HFD+TP, 41.8 g TP/kg diet, equivalent to 36 mg lycopene/day in human, which is 3–4 times higher than the average intake of lycopene) for 24 weeks. BCO1/BCO2 double KO mice (n=9) of the same age were fed with a chow diet as the control group.Results showed that TP supplementation significantly decreased hepatic steatosis and HCC development (67% reduction in incidence, 83% reduction in multiplicity, and 95% reduction in tumor volume) in BCO1/BCO2 double KO mice, as compared with the mice fed with HFD alone. The protective effects of TP supplementation were associated with 1) decreased hepatic inflammatory foci (89% reduction) and mRNA expressions of pro‐inflammatory biomarkers [interleukin (IL)‐6, IL‐12a, monocyte chemoattractant protein‐1, and inducible NO synthase]; 2) increased mRNA expressions of deacetylase sirtuin 1, sirtuin 3, and nicotinamide phosphoribosyltransferase involving NAD+ production; and 3) restored HFD‐reduced circadian clock gene expressions (circadian locomotor output cycles kaput, period 2, and cryptochrome‐2) to the normal levels of the control group. Taken together, the present study demonstrates that dietary TP can effectively inhibit HFD‐promoted steatosis, inflammation and tumorigenesis in the absence of BCO1/BCO2. The protective effects of TP against HFD‐induced liver injury may involve the regulations of sirtuin deacetylation and its related molecular clock function.Support or Funding InformationSupported by USDA/NIFA (2015‐67017) and USDA/ARS (58‐1950‐0014)