The role of the paraoxonase gene family in obesity and obesity-associated liver disease following exposure to environmental pollutants or medical intervention strategies.

Obesity constitutes a major health problem, partly due to the increasing prevalence and secondly because of its associated morbidity. It is associated with increased amounts of adipose tissue as well as fat accumulation in non-adipose tissue such as liver and skeletal muscle. Accumulation of ectopic fat in the liver (non-alcoholic fatty liver disease, NAFLD) is a strong independent marker of dyslipidaemia and insulin resistance predisposing to the development of type 2 diabetes. Besides high caloric diet and lack of physical activity, pesticide exposure and endocrine disruptor pollutants are now also increasingly recognized as an "obesogenic" risk factor. Remarkably, recent genome- and epigenome wide associations studies highlight crosstalk of many obesity-associated genetic variants and environmental factors (diet, pesticides, exercise, alcohol consumption, smoking, drugs, medication) with DNA methylation changes at proximal promoters and enhancers. For example, we recently found a strong association between the paraoxonase 1 (PON1) p.Q192R genotype with pesticide exposure and adverse epigenetic (re)programming of endocrine pathways in obesity and high body fat content. PON members hydrolyze several pesticides, a number of exogenous and endogenous lactones and metabolizes toxic oxidized lipids of low density lipoproteins (LDL) and HDL. A decrease in PON1 expression promotes adverse lipid metabolism and is an important risk factor for cardiometabolic disease and has recently been found to be associated with childhood and adult obesity, liver steatosis and its more severe subtype of steatohepatitis. Differences in PON2 have been associated with obesity susceptibility in brown/white adipose tissue. Given the crucial role of PON members in protecting from adverse environmental exposure and from obesity, there is an urgent need for further molecular and clinical research on (epi)genetic PON(1-3) regulation mechanisms in this area. In this GOA, we want to further investigate associations of clinical characterized obesity phenotypes with PON(1-3) genetic variants/polymorphisms, associated epigenetic DNA methylation variation and PON(1-3) expression in samples (i.e. blood, serum, adipose or liver) of clinical patient cohorts diagnosed with obesity, NAFLD/NASH, in relation to adverse pesticide exposure or following therapeutic medical intervention (liraglutide or bariatric surgery). Functional investigation of genetic-epigenetic regulatory crosstalk of PON(1-3) expression in response to pollutant exposure or following medical interventions will be further investigated in relation to biochemical parameters of obesity/liver steatosis/adipocyte differentiation in cell models in vitro as well as in zebrafish in vivo. As such, a better understanding of variable PON(1-3) regulation of obesity-associated traits by adverse obesogenic pollutants or healthy intervention strategies may offer new perspectives to prevent obesity and/or promote cardiometabolic health.

Keywords:LIVER STEATOSIS, EPIGENETICS, OBESITY, GENETICS

Disciplines:Epigenetics, Endocrinology