Genomic Instability in Liver Cells Caused by an LPS-Induced Bystander-Like Effect

Abstract

Bacterial infection has been linked to carcinogenesis, however, there is lack of knowledge of molecular mechanisms that associate infection with the development of cancer. We analyzed possible effects of the consumption of heat-killed E. coli O157:H7 cells or its cellular components, DNA, RNA, protein or lipopolysaccharides (LPS) on gene expression in naïve liver cells. Four week old mice were provided water supplemented with whole heat-killed bacteria or bacterial components for a two week period. One group of animals was sacrificed immediately, whereas another group was allowed to consume uncontaminated tap water for an additional two weeks, and liver samples were collected, post mortem. Liver cells responded to exposure of whole heat-killed bacteria and LPS with alteration in γH2AX levels and levels of proteins involved in proliferation, DNA methylation (MeCP2, DNMT1, DNMT3A and 3B) or DNA repair (APE1 and KU70) as well as with changes in the expression of genes involved in stress response, cell cycle control and bile acid biosynthesis. Other bacterial components analysed in this study did not lead to any significant changes in the tested molecular parameters. This study suggests that lipopolysaccharides are a major component of Gram-negative bacteria that induce molecular changes within naïve cells of the host.

Kynurenic Acid and Its Analog SZR104 Exhibit Strong Antiinflammatory Effects and Alter the Intracellular Distribution and Methylation Patterns of H3 Histones in Immunochallenged Microglia-Enriched Cultures of Newborn Rat Brains

“…They showed that not all cell lines released histones from nucleosomes during DNA fragmentation and apoptosis, while Gabler et al [32] demonstrated that the cytoplasmic accumulation of histones and nucleosomes in physiological cells was a precursor to apoptosis, occurring in parallel with the initial phagocytosis signals. During microglia activation by LPS, for instance, DNA damage and genome instability were observed [52,53]. Unmodified H2B in the cytoplasm acts as a sensor that detects double-stranded DNA fragments derived from infectious agents or damaged cells and as a consequence activates innate and acquired immune responses in various cell types [54,55].…”

Introductory Chapter: Obesity—“OMICS” and Endocrinology

“…The LPS-stimulated biological effect on p53-induced apoptosis in the liver [53,54] surpasses the effect of Sirt1 as to the deacetylation of p53, reducing the hepatic lipid turnover. Hence, the p53-mediated downregulation of PXR activity [55,56] is not dependent of the Sirt1/PXR-mediated reactions [57][58][59][60].…”

“…Sirt1 and its posttranscriptional impact on p53 [42,43] is heavily involved in the differentiation of adipocytes, as well as lipid metabolism in general [44][45][46][47][48], with their implications for abnormal Sirt1 deacetylation of p53, linked to lipid metabolism with its characteristic transformation of adipocytes and ensuing liver disease. Interestingly, both Sirt1 and p53 knockout mice develop NAFLD [49][50][51][52], which alludes to a close connections between adipocyte phenotype "switch" involving Sirt 1 and/or p53 impact on mitochondrial functioning [53][54][55][56].…”

LPS Regulates Apolipoprotein E and A<i>β</i> Interactionswith Effects on Acute Phase Proteins and Amyloidosis

“…LPS induction of APPs are linked to the CD14 receptor with the levels linked to liver inflammation and NAFLD [31]. LPS has been shown to effect hepatic genomic stability [32] with effects on reverse cholesterol transport in macrophages [4] and with macrophage activation [33]. LPS can rapidly insert into cell membranes with a preference for insertion and partition into cholesterol/ sphingomyelin domains in cell membranes [34]- [36].…”