Abstract
Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD.
Highlights
Fatty liver disease (FLD) is a growing health issue and is already the leading cause of liver damage worldwide[1]
In the Dallas Heart Study (DHS), rs71519934 was found as rs7003060, that is, in complete linkage disequilibrium with rs71519934 (D′ = 1, r2 = 1). bMAF EUR refers to 1000 Genome data reported in the Database of Single Nucleotide Polymorphisms (dbSNP), except for rs71519934 where the frequency was estimated in white British participants from the United Kingdom (UK) Biobank 50,000 exome sequencing data because data were not available in dbSNP. cGenotyping of Glucokinase regulator (GCKR) was undetermined in two individuals
All missense and nonsense variants in the genes identified by the tag single-nucleotide polymorphisms (SNPs) were tested for association with liver fat content in the DHS14 using linear regression analysis under an additive genetic model adjusted for age, gender and the top four principal components of ancestry
Summary
Fatty liver disease (FLD) is a growing health issue and is already the leading cause of liver damage worldwide[1]. Of 32 loci identified by a previous genome-wide association study on circulating triglyceride levels, three missense variants with a MAF >5% in Europeans were nominally associated with hepatic triglyceride content in the DHS cohort. Of these three variants, one was associated with a decrease in hepatic fat content (rs71519934, beta = −0.02), and two were associated with increased hepatic fat content (rs1260326, beta = 0.03 and rs58542926, beta = 0.12). Genetic variations in Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and other lipid droplet-related genes contribute to an increased risk of FLD onset and progression[12–16] These genetic variations affect hepatic lipid handling in the liver by altering lipid secretion, lipid droplet remodelling or by increasing de novo lipogenesis, and result in liver inflammation and fibrosis[17]. Despite recent progress in the field, the common variants identified to date account for less than 6% of the disease variability[17]
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