Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Nat Metab. 2022 Jan;4(1):60-75. doi: 10.1038/s42255-021-00518-0. Epub 2022 Jan 31.
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.
脂肪肝疾病（FLD）是一个日益严重的健康问题，存在未满足的临床需求。FLD 有遗传成分，但尽管已经确定了常见的变异体，仍然存在遗传缺失的成分。我们使用候选基因方法，在 Pleckstrin 和 Sec7 结构域包含 3（PSD3）基因中发现了一个位点（rs71519934），导致蛋白质第 186 位的亮氨酸到苏氨酸取代（L186T），降低了个体易感性在风险中发生的整个 FLD 谱。通过短干扰 RNA 下调 PSD3 可降低在二维和三维培养的原代人肝细胞以及人肝癌细胞和啮齿动物肝癌细胞中的细胞内脂质含量。与此一致，体内使用反义寡核苷酸下调 Psd3 可防止非酒精性脂肪性肝炎诱导饮食喂养的小鼠发生 FLD。因此，将这些结果转化为人类，下调 PSD3 可能成为治疗 FLD 的未来治疗选择。
