Lycopene Metabolite, Apo-10′-Lycopenoic Acid, Inhibits Diethylnitrosamine-Initiated, High Fat Diet–Promoted Hepatic Inflammation and Tumorigenesis in Mice

Abstract

Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10′-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9′,10′-double bond by carotene-9′,10′-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose-dependently inhibited cell growth and up-regulated sirtuin 1 (SIRT1), a NAD+-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)-promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation (decreased inflammatory foci, TNFα, IL-6, NF-κB p65 protein expression, and STAT3 activation) in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene and protein expression, and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, this data indicates that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation.

Lycopene Improves Diet-Mediated Recuperation in Rat Model of Nonalcoholic Fatty Liver Disease

“…All changes obtained in rats after 4 weeks of being fed with HFD are reported in results, and have been repeatedly found in previous studies, [16][17][18][19][20][21][22]25 and allowed us to properly assay the therapeutic efficacy of ND plus LYC against ND alone.…”

“…[9][10][11][12] Potential health benefits of lycopene (LYC) have been studied for more than 75 years. 7,13,14 In particular, experimental studies have shown that LYC supplementation effectively prevents the development of various liver injuries 15 : Animals were fed during several weeks with a high-fat diet (HFD) and supplemented with LYC, [16][17][18] an LYC metabolite, 16,19,20 or tomato juice as a source of LYC, 21,22 to prevent diet-mediated steatosis, 16,18,22 diethylnitrosamine-initiated HFD-promoted hepatocarcinoma, 17,19,20 and a metabolic pattern from an HFD. 21 The aim of this study was to assess the ability of LYC to return liver steatosis and to revert hepatic morphological changes produced by an HFD.…”

Carotenoid derivatives inhibit nuclear factor kappa B activity in bone and cancer cells by targeting key thiol groups

“…This mono acid derivative (10 0 -apo-lycopenoic acid) was found to have other biologic activities such as suppression of lung tumorigenesis associated with modulation of cell cycle proteins such as p21and p27 [67]. Recently, the inhibitory effect of 10 0 -apo-lycopenoic acid on high fat dietpromoted hepatic inflammation and tumorigenesis was reported by Ip et al [68] who observed an elevation of the level of the sirtuin deacetylase sirt1 associated with reduced acetylation of target proteins including the NFkB active subunit p65; a reduction in the total level of p65 was noted. These results suggest that different lycopene metabolites (e.g., acids versus aldehydes) could inhibit the NFkB pathway by different mechanisms.…”

Lycopene and Apo-10′-lycopenoic Acid Have Differential Mechanisms of Protection against Hepatic Steatosis in β-Carotene-9′,10′-oxygenase Knockout Male Mice

“…Evidence suggests that these metabolites may exhibit more important biological roles than lycopene itself (9,14,15), and BCO2 ablation in mice altered lycopene metabolism (16,17). In particular, APO10LA supplementation was effective in inhibiting hepatic steatosis in genetically induced obese (ob/ob) mice (15) and attenuating high saturated fat diet (HSFD)-induced liver inflammation as well as tumor number and volume in C57Bl/6J mice (18). An important question remains as to whether the biological activity of lycopene could be different from its metabolite APO10LA in the absence of BCO2 expression.…”