2019 Anitschkow Award given for defining genetic determinants of plasma lipid levels and CV risk

News - May 27, 2019

The Anitschkow Award is given for outstanding research in the field of atherosclerosis and linked metabolic disturbances and this year’s recipient is Professor Helen Hobbs. More specifically, she is awarded for her important work in defining the genetic determinants of plasma lipid levels and CV risk.

Hobbs is an Investigator of the Howard Hughes Medical Institute and a Professor of Internal Medicine and Molecular Genetics at the University of Texas Southwestern Medical Center. She is also Director of the Dallas Heart Study, a longitudinal, multi-ethnic, population-based study of Dallas County.

During a plenary session at the 87th EAS Congress, she eluded on her work on non-alcoholic fatty liver disease (NAFLD), which may progress to hepatocellular carcinoma in some individuals. Her research focusses on the role of lipids in this process. In the Dallas Heart Study, 5.5% of participants have hepatic TG content that fulfil the definition of hepatic steatosis. It was noted that the prevalence differed among blacks, whites and Hispanics, which could not be explained by known participant characteristics. Thus, Hobbs and her team set out to investigate how these differences arise.

Much of her research efforts focus on genetic variations that confer susceptibility to fatty liver disease. In genome-wide association studies, professor Hobbs identified a single nucleotide polymorphism (SNP) in patatin-like phospholipase domain–containing protein 3 (PNPLA3). This SNP was found to be the most important genetic risk factor for fatty liver disease. PNPLA3 resembles PNPLA2, the major intracellular TG hydrolase. They hypothesized and determined that PNPLA3 also functions as a lipase.

This SNP in PNPLA3 is associated with an increase in hepatic triglyceride content. In data of the Dallas Heart Study, they revealed that this relation is subject to a prominent gene-environment interaction, such that even if someone is homozygous for the risk allele, staying lean protects them from the disease. Moreover, the effect of this variant is substantially amplified by obesity and insulin resistance.

With experimental research in mouse models, Hobbs and colleagues unravelled how the mutated PNPLA3 leads to hepatic steatosis, and which interactions and processes (reduced proteosomal degradation) are involved. These insights yield several options to lower expression of PNPLA3, as a novel therapeutic strategy. This could for instance be achieved by knocking down PNPLA3 mRNA, or promoting ubiquitylation of the protein to enhance proteosomal degradation, or blocking the necessary protein interactions.

Our reporting is based on the information provided at the EAS 2019 congress

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