Abstract

Increased prevalence of non-alcoholic fatty liver disease (NAFLD) is one of the consequences of the current obesity epidemic. NAFLD is a major form of chronic liver disease that is highly prevalent in obese and overweight adults and children. Nonalcoholic steatohepatitis (NASH) is the severe form of NAFLD, and uncontrolled inflammation as displayed in NASH has been identified as one of the key events in enhancing hepatic carcinogenesis. Lycopene is a non-provitamin A carotenoid and the pigment principally responsible for the characteristic deep-red color of ripe tomato and tomato products, as well as some fruits and vegetables. Lycopene’s innate antioxidant and anti-inflammatory properties have generated research interests on its capacity to protect against human diseases that are associated with oxidative stress and inflammation. In addition, differential mechanisms of lycopene metabolism including endogenous cleavage by carotenoid cleavage oxygenases (BCOs), generate lycopene metabolites that may also have significant impact on human disease development. However, it remains to be elucidated as to whether lycopene or its metabolites apolycopenoids have protective effects against obesity-related complications including inflammation and tumorigenesis. This article summarizes the in vivo experiments that elucidated molecular mechanisms associated with obesity-related hepatic inflammation and carcinogenesis. This review also provides an overview of lycopene metabolism, and the molecular pathways involved in the potential beneficial properties of lycopene and apolycopenoids. More research is clearly needed to fully unravel the importance of BCOs in tomato carotenoid metabolism and the consequence on human health and diseases.

Highlights

  • Liver cancer is the third leading cause of cancer-related deaths worldwide [1,2,3], and the most frequent and aggressive primary liver tumor is hepatocellular carcinoma (HCC) [1,2,3]

  • HCC’s escalating morbidity and mortality trends parallel to the rising prevalence of non-alcoholic fatty liver disease (NAFLD), a chronic liver disease that is observed in 75%–100% of overweight and obese adults and children [8,9,10], and describes a range of related disorders that can progress in stages [11]

  • free fatty acids (FFA) can associate with fetuin A (FetA) released from the liver and activate TLR4-mediated proinflammatory signaling in adipocyte and Mɸ, creating a feed-forward mechanism in promoting further systemic and hepatic inflammation

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Summary

Introduction

Liver cancer is the third leading cause of cancer-related deaths worldwide [1,2,3], and the most frequent and aggressive primary liver tumor is hepatocellular carcinoma (HCC) [1,2,3]. Hepatic inflammation and injury in NASH are effective in activating hepatic stellate cells, which are specialized cells that involve in liver regeneration, but they can promote cirrhosis by replacing hepatocytes with type I collagen-rich scar tissue [7,11]. This event results in an environment that is permissive to genetic modulations and exogenous impacts leading to neoplastic transformation [7,12]. HCC has extraordinary heterogeneity of genomic aberrations [13], but more than 90% of HCC develops based on chronic inflammation as displayed in NASH [13] Such evidence highlights the critical role of hepatic inflammation in NAFLD associated hepatocarcinogenesis.

GI Tract
Adipose Tissue
Other Systemic Perturbations
Lipid Metabolism
ER Stress
ROS and CYP-P450 Enzymes
Inflammation and TLR4
Tomato Effects
Lycopene Effects
Lycopene Metabolism
Chemical Oxidation
Oxidative Metabolism in Plants
Oxidative Metabolism in Mammals
Potential Alternative Pathways
Oxidation of Apolycopenoids
Effects of Apolycopenoids
Potential Molecular Mechanisms
Modulating Pro-Inflammatory Signaling and Cytokine Expression
Antioxidant Mechanism
Retinoid Receptors Interactions
Anti-Metastatic Effects
SIRT1 Up-Regulation
Findings
Conclusions
Full Text
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