Carotenoids and Retinoids (CARIG)
Objectives : Reverse cholesterol transport (RCT), which mediates removal of excess cholesterol from peripheral tissues, is a key player in persistent lung inflammation, a common feature of chronic obstructive pulmonary disease (COPD) and lung cancer, after cigarette smoke (CS) exposure. We have previously shown that lycopene, a carotenoid naturally occurring in tomatoes and tomato products, inhibits tobacco carcinogen (NNK)/CS-induced COPD and preneoplastic lesions in lung of ferrets, but the mechanism is unknown. We hypothesize that the protective role of lycopene against NNK/CS-induced COPD and lung preneoplastic lesions is associated with restoring the RCT in ferrets.
Methods : Male ferrets (4 groups, n=12−16/group) were exposed to combination of NNK and CS with or without lycopene feeding at low (LL) and high (HL) doses (equivalent to ~30 mg and ~90 mg lycopene/day in humans, respectively) for 22 weeks. Ferrets in NNK/CS groups were given NNK (50 mg/kg body weight, i.p. injection) once a month for 4 consecutive months, and were exposed to CS for 30 min/day for 22 weeks. The animals were fed lycopene or placebo starting three weeks prior to the NNK injections and continued until the end of the study.
NNK/CS exposure significantly increased total cholesterol levels in both plasma and lungs of ferrets (P < 0.05), which was associated with COPD and lung preneoplastic lesion development. In lungs, HL and LL doses lowered NNK/CS-induced total cholesterol, with HL dose reaching significance (P < 0.05); this was accompanied with the decreased lung lesions. HL group had significantly higher mRNA expression of critical genes involved in RCT (LXRα, PPARα, ABCA1 and ABCG1) as compared to NNK/CS group (P < 0.05). Additionally, HL feeding significantly increased protein levels of both nuclear hormone receptors, LXRα and PPARα, known regulators of ABCA1/G1 transporters (P < 0.05). In plasma, lycopene restored total cholesterol and HDL-C concentrations to normal. Plasma triglyceride, LDL-C and VLDL-C concentrations were not significantly different between groups.
Conclusions : These data demonstrate an important association between lycopene protection against NNK/CS induced lung lesions and pulmonary cholesterol homeostasis through the restoration of the impaired RCT.
Funding Sources : NIH/NCI, USDA/ARS grants