HSD17B13 and MARC1 - Understanding genetic protection from non-alcoholic fatty liver disease

• Applicant: Professorin Dr. Carolin Victoria Schneider
• Subject Area: Gastroenterology ; Human Genetics
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448210878

The non-alcoholic fatty liver disease (NAFLD) pandemic has reached alarming magnitudes, affecting nearly 2 billion people worldwide. In the past 10 years, genome-wide association studies have revealed several single nucleotide polymorphisms (SNPs) associated with increased risk of NAFLD (e.g. PNPLA3 or TM6SF2). Still, it is poorly understood which factors are driving NAFLD progression. Last year, a splice variant of HSD17B13 (rs72613567:TA) encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was found to be protective against NAFLD development and progression from steatosis to steatohepatitis. Little is known about the function of HSD17B13 and still the mechanism by which loss of function variants protect against NAFLD development and progression are unknown. Recently, another loss-of-function variant (MARC1 p.A165T) which protects against NAFLD progression was discovered. MARC1, the Mitochondrial Amidoxime Reducing Component 1 gene encodes an enzyme that is involved in metabolic processes in the liver. The exact function of the protein encoded by MARC1 is unknown and the mechanism by which MARC1 p.A165T may protect from liver damage and cirrhosis remain elusive. Neither MARC1 p.A165T nor HSD17B13 rs72613567:TA are associated with an altered risk of cardiovascular diseases (in contrast to PNPLA3 or TM6SF2) and therefore appear to be specific to liver biology. Inhibition of these proteins could be used as promising targets for future therapies to reduce risk of NAFLD and its consequences. With the unique possibility of the Penn medicine biobank we will enroll a prospective study to elucidate the phenotype of patients carrying protective HSD17B13 or MARC1 loss of function variants (pLoF) and to use human studies to gain insight into the molecular mechanisms by which predicted pLoF variants in HSD17B13 and MARC1 can protect against fatty liver disease. We will characterize the detailed phenotypes of individuals with HSD17B13 or MARC1 pLoF by using a recall-by-genotype approach to understand their effect on the liver phenotype. Further insights in the mechanisms of protection against NAFLD will be obtained by analyzing metabolomic information in these patients, which could reveal potential targets and biomarkers. We will generate iPS cells from patients with HSD17B13 or MARC1 pLoF variants, differentiate them into hepatocyte-like cells (HCLs) and phenotype their enzymatic activity and metabolic function to reveal potential targetable pathways. In a last step we will use serum samples of NAFLD patients and controls to identify metabolites in these targetable pathways as potential NAFLD biomarkers.By combining results of metabolomics with detailed clinical data, this project will shed new light into the pathophysiology of NAFLD development and progression. The development of companion biomarkers will improve stratification of NAFLD patients and personalization of treatment to ultimately reduce mortality.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Daniel J Rader