Abstract
Both incidence and death rate due to liver cancer have increased in the United States. Higher consumption of lycopene-rich tomato and tomato products is associated with a decreased risk of cancers. β-Carotene-15, 15'-oxygenase (BCO1), and β-carotene-9', 10'-oxygenase (BCO2) cleave lycopene to produce bioactive apo-lycopenoids. Although BCO1/BCO2 polymorphisms affect human and animal lycopene levels, whether dietary tomato consumption can inhibit high-fat diet (HFD)-promoted hepatocellular carcinoma (HCC) development and affect gut microbiota in the absence of BCO1/BCO2 is unclear. BCO1/BCO2 double knockout mice were initiated with a hepatic carcinogen (diethylnitrosamine) at 2 weeks of age. At 6 weeks of age, the mice were randomly assigned to an HFD (60% of energy as fat) with or without tomato powder (TP) feeding for 24 weeks. Results showed that TP feeding significantly decreased HCC development (67%, 83%, and 95% reduction in incidence, multiplicity, and tumor volume, respectively, P < 0.05). Protective effects of TP feeding were associated with (1) decreased hepatic inflammatory foci development and mRNA expression of proinflammatory biomarkers (IL1β, IL6, IL12α, monocyte chemoattractant protein-1, and inducible NO synthase); (2) increased mRNA expression of deacetylase sirtuin 1 and nicotinamide phosphoribosyltransferase involving NAD+ production; and (3) increased hepatic circadian clock genes (circadian locomotor output cycles kaput, period 2, and cryptochrome-2, Wee1). Furthermore, TP feeding increased gut microbial richness and diversity, and significantly decreased the relative abundance of the genus Clostridium and Mucispirillum, respectively. The present study demonstrates that dietary tomato feeding independent of carotenoid cleavage enzymes prevents HFD-induced inflammation with potential modulating gut microbiota and inhibits HFD-promoted HCC development.
Highlights
Nonalcoholic fatty liver disease (NAFLD) affects 30%, 20%, and 3% to 10% of adult men, women, and chil-H
We observed that mRNA expression of the circadian rhythm–related gene expression including Clock, Cry2, Per2, and Wee1 was more significantly upregulated in the DENþHFDþTP group than in the DENþHFD group in Fig. 2F, indicating potential regulating effects of tomato powder (TP) on sirtuin 1 (SIRT1)/circadian clock/nicotinamide phosphoribosyltransferase (NAMPT) axis in the liver of mice
The average steatosis score for the DENþHFDþTP group was significantly lower than the DENþHFD group in Fig. 3A and B, which suggest TP feeding suppressed the development of hepatic steatosis
Summary
About 3% of NAFLD can progress to the inflammatory stage, nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and liver failure, in which a liver transplant is a patient's only hope, and end-stage liver disease, such as primary liver cancer Both incidence and death rate of liver cancer have increased in the United States [3]. The future burden of liver cancer in 30 countries around 2030 has been predicted: the largest increases in rates are in the United States [4]. Given the poor prognosis and high mortality rate of HCC, and no effective therapeutic agent that can halt the development and progression of HCC, it is important to discover a diet rich in effective chemopreventive agents against HCC development
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