Inhibition of diethylnitrosamine-initiated alcohol-promoted hepatic inflammation and precancerous lesions by flavonoid luteolin is associated with increased sirtuin 1 activity in mice

Background: Chronic and excessive alcohol consumption is an established risk for hepatic inflammationand carcinogenesis. Luteolin is one of the most common flavonoids present in plants and has potentialbeneficial effects against cancer. In this study, we examined the effect and potential mechanisms of luteolinsupplementation in a carcinogen initiated alcohol-promoted pre-neoplastic liver lesion mouse model.Methods: C57BL/6 mice were injected with diethylnitrosamine (DEN) [i.p. 25 mg/kg of body weight (BW)]at 14 days of age. At 8 weeks of age mice were group pair-fed with Lieber-DeCarli liquid control diet oralcoholic diet [ethanol (EtOH) diet, 27% total energy from ethanol] and supplemented with a dose of 30 mgluteolin/kg BW per day for 21 days.Results: DEN-injected mice fed EtOH diet displayed a significant induction of pre-neoplastic lesions, amarker associated with presence of steatosis and inflammation. Dietary luteolin significantly reduced theseverity and incidence of hepatic inflammatory foci and steatosis in DEN-injected mice fed EtOH diet, as wellthe presence of preneoplastic lesions. There was no difference on hepatic protein levels of sirtuin 1 (SIRT1)among all groups; however, luteolin supplementation significantly reversed alcohol-reduced SIRT1 activityassessed by the ratio of acetylated and total forkhead box protein O1 (FoXO1) and SIRT1 target proliferatoractivatedreceptor gamma, coactivator 1 alpha (PGC1α).Conclusions: Dietary intake of luteolin prevents alcohol promoted pre-neoplastic lesions, potentiallymediated by SIRT1 signaling pathway.