Dietary lycopene attenuates cigarette smoke-promoted nonalcoholic steatohepatitis by preventing suppression of antioxidant enzymes in ferrets

Authors: MUSTRA RAKIC, JELENA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; VEERAMACHANENI, SUDIPTA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PAUL, LIGI - Tufts University; AUSMAN, LYNNE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/31/2020
Publication Date: 5/1/2021
Citation: Mustra Rakic, J., Liu, C., Veeramachaneni, S., Wu, D., Paul, L., Ausman, L., Wang, X. 2021. Dietary lycopene attenuates cigarette smoke-promoted nonalcoholic steatohepatitis by preventing suppression of antioxidant enzymes in ferrets. Journal of Nutritional Biochemistry. 91(2021):108596. https://doi.org/10.1016/j.jnutbio.2021.108596.
DOI: https://doi.org/10.1016/j.jnutbio.2021.108596

Interpretive Summary: This study demonstrates that cigarette smoke can promote development of fatty liver disease in the ferret, a good model to mimic human carotenoid absorption and metabolism. Using this model, we demonstrated that dietary lycopene can inhibit cigarette smoke-promoted fatty liver disease by preventing suppression of the antioxidant network.

Technical Abstract: Cigarette smoke (CS) is an independent risk factor in development of nonalcoholic steatohepatitis (NASH) and fibrosis. Lycopene, a carotenoid naturally occurring in tomatoes, has been shown to be a protective agent against tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced NASH. In the present study using a ferret model we investigated whether CS promotes NASH and whether dietary lycopene can inhibit CS-promoted NASH development, and if so, what potential mechanisms were involved. Ferrets were divided into 4 groups (n=12-16/group): control, NNK/CS exposed, NNK/CS plus low-dose lycopene (2.2 mg/kg BW/day), and NNK/CS plus high-dose lycopene (6.6 mg/kg BW/day) groups, for 26 weeks. Results showed that hepatic steatosis, infiltrates of inflammatory cells, and the number and size of inflammatory foci in liver, together with key genes involved in hepatic fibrogenesis were higher in the NNK/CS group compared to the control group; a lycopene diet reversed these changes to the levels of the control group. Interestingly, a major lycopene cleavage enzyme, beta-carotene 9',10'-oxygenase (BCO2), which recently has been recognized to play metabolic roles beyond cleavage function, was down-regulated by NNK/CS exposure, but this decrease was prevented by lycopene feeding. NNK/CS exposure also downregulated liver expression of antioxidant enzymes and upregulated oxidative stress marker, which were all prevented by lycopene. In conclusion, our results suggest that CS can promote development of NASH and liver fibrosis in ferrets, which is associated with downregulation of BCO2 and impairment of antioxidant system in liver; dietary lycopene may inhibit CS-promoted NASH by preventing suppression of BCO2 and decline in antioxidant network.