Lycopene metabolite, apo‐10′‐lycopenoic acid, inhibits diet‐induced obesity‐promoted liver carcinogenesis via the up‐regulation of SIRT1 signaling and the decrease in liver inflammation.

Abstract

Chronic inflammation caused by diet induced‐obesity (DIO) is associated with increased liver cancer risk. We previously demonstrated that dietary lycopene ameliorated DIO‐promoted liver precancerous lesions, while supplementation of lycopene's cleavage metabolite, apo‐10′‐lycopenoic acid (APOLA), upregulated hepatic sirtuin 1 (SIRT1) activity. SIRT1 is a NAD‐dependent deacetylase that inhibits DIO‐promoted liver inflammation and carcinogenesis when overexpressed. This study aimed to elucidate the chemopreventative effects of APOLA and associated SIRT1 signaling with in‐vitro and in‐vivo models. APOLA treatment in immortalized liver cells upregulated SIRT1 expression and AMP‐activated protein kinase‐á (AMPKá) phosphorylation in a dose‐dependent manner. Dietary APOLA at 10 mg/kg of diet for 24 weeks significantly reduced carcinogen‐initiated, DIO‐promoted liver cancer (in tumor multiplicity and volume) and lung tumor incidence in C57BL/6J mice. These outcomes were associated with reduced liver inflammation (decreased cleavage of caspase‐1, IL‐6, TNFá, NF‐êB p65 protein expression, and inflammatory foci), and increased hepatic AMPKá phosphorylation, SIRT1 protein expression and its deacetylase activity. Taken together, this present study revealed that APOLA inhibits DIO‐promoted liver carcinogenesis by stimulating AMPK‐SIRT1 signaling and reducing liver inflammation.Grant Funding Source: USDA/ARS Grant 1950–51000‐064S