High-fat diet modifies expression of hepatic cellular senescence gene p16(INK4a) through chromatin modifications in adult male rats

Abstract

BackgroundLiver is the crucial organ as a hub for metabolic reactions. p16(INK4a) is a well-established cyclin-dependent kinase (CDK) inhibitor that plays important role in the molecular pathways of senescence, which lead to irreversible cell cycle arrest with secretion of proinflammatory cytokines and mitochondrial dysfunction. This study tested the hypothesis that cellular senescence regulated by p16(INK4a) is associated with high-fat diet in adult male rats.MethodsSprague Dawley rats were fed a high-fat (HF) diet or a control (C) diet for 9 weeks after weaning. At 12 weeks of age, liver samples of male rats were collected to investigate the key genes and liver physiological status.ResultsBoth mRNA and protein expression level of cellular senescence marker, p16(INK4a), was increased significantly in HF group when compared to C group. A decrease of tri-methylated histone H3 lysine 27 (H3K27Me3) in the coding region of p16(INK4a) was observed. On the other hand, mRNA and protein expression of another inhibitor of cyclin-dependent kinase, p21(Cip1), was decreased significantly in HF group; however, no significant chromatin modification was found in this gene. Histological analysis demonstrated hepatic steatosis in HF group as well as severe fat accumulation.ConclusionsOur study demonstrated that HF diet regulated cellular senescence marker p16(INK4a) through chromatin modifications, which may promote hepatic fat accumulation and steatosis.

Histone Modifications as an Intersection Between Diet and Longevity

“…The p16(Ink4a ) gene showed higher H4ac and lower H3K27me levels at the promoter and/or the coding region in the liver of OP compared to OR mice ( Zhang et al, 2012 ). Similar results have been observed in p16(Ink4a ) expression when comparing OP to control mice ( Zhang et al, 2018 ). This is one of the earliest examples of how diet affects histone modifications, which in turn impact on specific genes that regulate cellular lifespan ( Zhang et al, 2012 ).…”

Potential Micronutrients and Phytochemicals against the Pathogenesis of Chronic Obstructive Pulmonary Disease and Lung Cancer

“…Histone modulations have been identified as an important chemoprevention target and HDAC inhibitors have been regarded as promising anti-cancer agents [ 109 ]. Diet is a modifiable factor for histone modulations and a high-fat diet is associated with chromatin modifications in animal models [ 110 , 111 ]. For now, short-chain fatty acids (SCFAs) are well-studied HDAC inhibitors, and dietary SCFAs were shown to be associated with the inhibition of HDAC activity in vitro [ 112 ].…”

D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway

“…The relative expression levels were presented as ΔCt = Ct gene-Ct reference, and fold changes of gene expression were calculated using the 2 -ΔΔCt method. The following primers were synthesized by Sangon Biotech and used for amplification: p16 , 5’-TGCAGATAGACTAGCCAGGGGA-3’ and 5’-CTTCCAGCAGTGCCCGCA-3’ [ 59 ]; NF-κB , 5’-CATCCACCTTCATGCTCAGC-3’ and 5’- CCACCACATCTTCCTGCTTG-3’[ 60 ]; CYR61 , 5’-CTCAACGAGGACTGCAGCAA-3’ and 5’-CAGGGTCTGCCTTCTGACTGA-3’[ 61 ]; CTGF , 5’-CCGCCAACCGCAAGATT-3’ and 5’-CACGGACCCACCGAAGAC-3’[ 62 ]; β -actin, 5’-AAGTCCCTCACCCTCCCAAAAG-3’ and 5’- AAGCAATGCTGTCACCTTCCC-3’ [ 63 ]; GAPDH , 5’-AACTTTGGCATCGTGGAAGGG-3’ and 5’- AGGGATGATGTTCTGGGCTGC-3’[ 64 ].…”