Abstract
Obesity is a complex disorder (with both lifestyle and genetic factors known to play a role in its development) affecting as much as 650 million people worldwide. Moreover, it induces excessive inflammation and oxidative stress and subsequently leads to the development of comorbidities such as non-alcoholic fatty liver disease (NAFLD). With a prevalance of 25% in general population and up to 90% in the obese population, NAFLD is currenty the most common chronic liver disease worldwide. On top of that, it can progress into life-threatening diseases such as liver cirrhosis. However, treatment options remain limited, especially for more advanced disease stages, indicating a need for better disease characterisation including elucidation of genetic risk factors that predispose to its development and early diagnosis. Consequently, in this project, we will investigate the role of the anti-inflammatory and anti-oxidative proteins paraoxonase (PON) 1 and 3, which are highly expressed in liver. To this end, our preliminary results showing a correlation between PON1 and NAFLD in an obesity cohort will be validated in a pon1 knockout model in zebrafish. PON3 will be examined in an in vitro HepG2 cell model and in a human obesity cohort. Ultimately, we will unravel the role of PON1 and PON3 in obesity and obesity-associated liver disease and elucidate the possible underlying mechanisms, being inflammation and oxidative stress.
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