UNDERSTANDING MOLECULAR GENETICS OF FATTY LIVER DISEASE

Fatty liver disease (FLD) is the leading cause of chronic liver disease and it will soon become the first cause of liver transplant.

Despite its prevalence, specific treatments for FLD are currently not available.FLD has a strong genetic component, and we identified PNPLA3 rs738409 (I148M) and MBOAT7 rs641738 as genetic variants that contribute to FLD progression.

PNPLA3 I148M increases the risk of FLD more than 8-fold and our preliminary results indicate that this risk is even higher in women.

MBOAT7 rs641738 reduces the expression of MBOAT7, and we showed that MBOAT7 deficiency may contribute to FLD by affecting a novel triglyceride synthesis pathway related to phospholipid turnover.

However, the enzyme responsible for this turnover has not been identified.The overall aim of this grant is to increase our understanding of molecular genetics of FLD.First, we will determine why the PNPLA3 I148M variant has a more deleterious effect in women and how reduced MBOAT7 expression affects the novel non-canonical hepatic triglyceride synthesis pathway.Second, we will verify if a novel common variant in PSD3 is associated with protection against FLD and elucidate the mechanisms behind this association.

We will also identify novel genetic determinants of FLD by examining rare variants increasing its susceptibility.Increased understanding of the molecular genetics of FLD is needed to identify effective therapeutic targets and will lead to the development of treatments to prevent FLD.