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Obesity and associated liver diseases

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Background

Obesity is an important health risk with an increasing prevalence. It is associated with fat accumulation in adipose tissue as well as ectopically in tissues such as liver and skeletal muscle. Ectopic fat accumulation in the liver (Non-Alcoholic Fatty Liver Disease, NAFLD) can be accompanied by chronic liver necroinflammation (Non-Alcoholic Steatohepatitis, NASH). It has become clear that NAFLD/NASH is not just a consequence of obesity, but is a driving force of both metabolic and cardiovascular derangements. The mechanisms and processes underlying the development of obesity are undoubtedly multifactorial in nature. First, numerous studies have shown that 40-70% of the interindividual variability in BMI can be attributed to genetic factors. Given the estimated heritability, extensive genome-wide association studies (GWASs) have been performed to identify common single-nucleotide polymorphisms (SNPs) possibly underlying the heritable risk for human obesity. Despite the fact that a large number of associated variants were identified, they only explain a small percentage of the genetic variability. Second, the dramatically increasing prevalence cannot be explained exclusively by genetic factors. The same holds true for NAFLD/NASH, for which several SNPs have been identified that, as background modifiers, explain part of the interindividual variation in presence and severity of these liver pathologies.

Goal

The aim of the research is to study the effect of genetic variants on the risk for obesity and their contribution in the development and progression of NAFLD/NASH.

Strategy

Thanks to long lasting clinical collaborations, samples from large cohorts of patients are available for study. A multi-omics approach is used including genomics, epigenomics and transcriptomics to identify and characterize genetic variants that could contribute to the pathogenesis of obesity and associated liver diseases. Furthermore in vitro functional studies are performed as well as zebrafish models are made to validate variants of potential interest.

Disorders under investigation



Team Members

Wim Van Hul, Evelien Van Dijck, Tammy Huybrechts, Ellen Steenackers


  • Obesity research (PhD student Evelien Van Dijck)
  • non-alcoholic fatty liver disease research (PhD student Tammy Huybrechts)

  • Unraveling the Role of Paraoxonase 1 and 3 in the Etiology and Progression of Obesity and Obesity-Associated Liver Disease

    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 prevalence of 25% in the general population and up to 90% in the obese population, NAFLD is currently 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 characterization including elucidation of genetic risk factors predisposing 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 the 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 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.

    PhD student: Evelien Van Dijck
    Promotors: Wim Van Hul, Wim Vanden Berghe, Dries Knapen & Sven Francque

    Evelien VD

  • The role of Paraoxonase 2 in the pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease

    Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the most common chronic liver disease with a worldwide prevalence up to 32,4%.The Paraoxonase gene family consists of 3 members (PON1, PON2, PON3) that have anti-inflammatory and anti-oxidative properties. We performed variant burden tests on single-molecule molecular inversion probes sequencing data of de coding regions of PON1, PON2 and PON3. We found an association between rare and very rare variants in PON2 (an important intracellular anti-oxidant enzyme) and fibrosis in an obesity cohort with and without the presence of MASLD. The aim of this project is to study the role of PON2 in fibrosis development in both an vitro and in vivo model. For the in vitro model a hepatic stellate cell line (LX-2) is used because this cell type is, once activated, responsible for fibrosis development. Using CRISPR-Cas9, a knock-out model will be generated and fibrosis development will be assessed via qPCR to determine the relative expression of fibrosis markers and a picrosirius red staining. To study the fibrosis development upon PON2 deficiency a pon2 KO zebrafish model will be generated and phenotyped via RNA sequencing, staining, qPCR.

    PhD student: Tammy Huybrechts
    Promotors: Wim Van Hul

    Tammy H

Team members - Hereditary obesity

Wim Van Hul
Wim Van Hul

Wim Van Hul

Wim Van Hul
Evelien Van Dijck
Evelien Van Dijck
PhD student

Evelien Van Dijck

PhD student

Evelien Van Dijck
Tammy Huybrechts
Tammy Huybrechts
PhD student

Tammy Huybrechts

PhD student

Tammy Huybrechts
Ellen Steenackers
Ellen Steenackers
Lab technician

Ellen Steenackers

Lab technician

Ellen Steenackers