ABSTRACT
Lycopene has been proven to alleviate nonalcoholic steatohepatitis (NASH), but the precise mechanisms are inadequately elucidated. In this study, we found a previously unknown regulatory effect of lycopene on the apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in both in vivo and in vitro models. Lycopene supplementation (3 and 6 mg/kg/day) exhibited a significant reduction in lipid accumulation, inflammation, and fibrosis of the liver in mice fed with a high-fat/high-cholesterol diet or a methionine-choline-deficient diet. RNA sequencing uncovered that the mitogen-activated protein kinases signaling pathway, which is closely associated with inflammation and endoplasmic reticulum (ER) stress, was significantly downregulated by lycopene. Furthermore, we found lycopene ameliorated ER swelling and decreased the expression levels of ER stress markers (i.e., immunoglobulin heavy chain binding protein, C/EBP homologous protein, and X-box binding protein 1s). Especially, the inositol-requiring enzyme 1α involved in the ASK1 phosphorylation was inhibited by lycopene, resulting in the decline of the subsequent c-Jun N-terminal kinase (JNK) signaling cascade. ASK1 inhibitor DQOP-1 eliminated the lycopene-induced inhibition of the ASK1-JNK pathway in oleic acid and palmitic acid-induced HepG2 cells. Molecular docking further indicated hydrophobic interactions between lycopene and ASK1. Collectively, our research indicates that lycopene can alleviate ER stress and attenuate inflammation cascades and lipid accumulation by inhibiting the ASK1-JNK pathway.
Subject(s)
MAP Kinase Signaling System , Non-alcoholic Fatty Liver Disease , Animals , Mice , MAP Kinase Signaling System/physiology , Lycopene/metabolism , MAP Kinase Kinase Kinase 5/genetics , MAP Kinase Kinase Kinase 5/metabolism , MAP Kinase Kinase Kinase 5/pharmacology , Molecular Docking Simulation , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/genetics , JNK Mitogen-Activated Protein Kinases/genetics , Inflammation/drug therapy , Inflammation/genetics , Endoplasmic Reticulum Stress , Lipids/pharmacology , ApoptosisABSTRACT
Chronic non-communicable diseases are the major cause of death globally. Whole grains are recommended in dietary guidelines worldwide due to increasing evidence that their consumption can improve health beyond just providing energy and nutrients. Epidemiological studies have suggested that the incorporation of whole grains, as part of a healthy diet, plays a key role in reducing one's risk for cardiovascular diseases (CVDs), obesity, type 2 diabetes (T2D) and cancer. Phenolic acids and dietary fibre are important components found in whole grains that are largely responsible for these health advantages. Both phenolic acids and dietary fibre, which are predominantly present in the bran layer, are abundant in whole-grain cereals and pseudo-cereals. Several studies indicate that whole grain dietary fibre and phenolic acids are linked to health regulation. The main focus of this study is two-fold. First, we provide an overview of phenolic acids and dietary fibres found in whole grains (wheat, barley, oats, rice and buckwheat). Second, we review existing literature on the linkages between the consumption of whole grains and the development of the following chronic non-communicable diseases: CVDs, obesity, T2D and cancer. Altogether, scientific evidence that the intake of whole grains reduces the risk of certain chronic non-communicable disease is encouraging but not convincing. Based on previous studies, the current review encourages further research to cover the gap between the emerging science of whole grains and human health.
