Prenatal Arsenic Exposure Alters Gene Expression in the Adult Liver to a Proinflammatory State Contributing to Accelerated Atherosclerosis

The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE−/−) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE−/− mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans

Association between PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), GCKR (rs780094), and elevated transaminase levels in overweight/obese Mexican adults

PURPOSE: There is scarce information about the link between specific single-nucleotide polymorphisms (SNPs) and risk of liver disease among Latinos, despite the disproportionate burden of disease among this population. Our aim was to investigate nine SNPs in or near the following genes: PNPLA3, LYPLAL1, PPP1R3B, GCKR, NCAN, IRS1, PPARG, and ADIPOR2 and examine their association with persistently elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels in Mexican adults. MATERIALS AND METHODS: Data and samples were collected from 741 participants in the Mexican Health Worker Cohort Study, in Cuernavaca, Mexico. We identified 207 cases who had persistently elevated levels of ALT or AST (≥40 U/L) and 534 controls with at least two consecutive normal ALT or AST results in a six month period, during 2006–2010 and 2011–2013. TaqMan assays were used to genotype the SNPs. RESULTS AND DISCUSSION: The risk allele of PNPLA3 rs738409 was found to be associated with persistently elevated levels of ALT or AST, adjusting for age, sex, BMI, type 2 diabetes, and ancestry: (OR = 2.28, 95% CI= 1.13, 4.58). A significant association was found between the LYPLAL1, PPP1R3B, and GCKR risk alleles and elevated ALT or AST levels among overweight/obese adults. CONCLUSION: These results suggest that among Mexicans, the PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) polymorphisms may be associated with a greater risk of chronic liver disease among overweight adults. This study is the first to examine these nine SNPs in a sample of Mexican adults

PARylation, DNA (de)methylation, and diabetes

Diabetes and diabetic complications, autoimmunity and inflammatory diseases, have recently become the focus of epigenetic therapy, since with epigenetic drugs it is possible to reverse aberrant gene expression profiles associated with the disease states. For diabetes, the therapy challenges depend on identifying the most appropriate molecular target and its influence on a relevant gene product. This chapter summarizes the current view on the interplay between ten-eleven translocation (TETs) and the poly(ADP-ribose) polymerase (PARPs) family of enzymes in regulating DNA methylation and how this interplay could be targeted to attenuate diabetes. This molecular interchange jigsaw puzzle is emerging as an important focus of research, and we can expect to see further advances in the elucidation of its role in diabetes as well as other pathologies. Moreover, the possibility for designating specific PARP-1 inhibitors as potential “EPI-drugs” for diabetes prevention/attenuation is also discussed. Understanding the epigenetic machinery and the differential roles of its components is essential for the development of targeted epigenetic therapies for diseases

Increased risk of cardiovascular disease and chronic kidney disease in NAFLD. [Review]

NAFLD is very common in the general population and its prevalence is increasing worldwide in parallel with the increasing incidences of obesity and metabolic diseases, mainly type 2 diabetes. In some cases, however, the diagnosis of NAFLD remains uncertain because other causes of liver disease are noteasy to exclude in patients who are diagnosed with NAFLD after a biochemical or ultrasonographic analysis.Several studies have documented a strong association between NAFLD and traditional and nontraditional risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Accordingly, patients with NAFLD have an increased prevalence and incidence of both CVD and CKD. It is reasonable to believe that NAFLD, CVD and CKD share common risk factors (such as visceral obesity, insulin resistance, dysglycaemia, dyslipidaemia and hypertension) and therefore that NAFLD might simply be a marker rather than a causal risk factor of CVD and CKD. In this context, the identification of NAFLD might be an additional clinical feature to improve the stratification of patients for their risk of CVD and CKD. Growing evidence suggests that in patients with NAFLD, especially if NASH is present, several molecules released from the steatotic and inflamed liver might have pathogenic roles in the development of atherosclerosis and kidney damage. If these findings are confirmed by further studies, NAFLD could become a target for the prevention and treatment of CVD and CKD. NAFLD, whatever its role (marker or causal risk factor), is therefore a clinical condition that deserves greater attention from gastroenterologists, endocrinologists, cardiologists and nephrologists, as well as internists and general practitioners