Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA.
University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Hepatol. 2023 Nov;79(5):1226-1235. doi: 10.1016/j.jhep.2023.07.036. Epub 2023 Aug 9.
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), and its progressive form steatohepatitis (NASH), represent a genetically and phenotypically diverse entity for which there is no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy with early-onset NAFLD/NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NAFLD.
Using hepatic steatosis as the outcome of interest, we performed an association meta-analysis of nuclear envelope-related coding variants in three large discovery cohorts (N >120,000 participants), followed by phenotype association studies in large validation cohorts (N >600,000) and functional testing of the top steatosis-associated variant in cell culture.
A common protein-coding variant, rs6461378 (SUN1 H118Y), was the top steatosis-associated variant in our association meta-analysis (p <0.001). In ancestrally distinct validation cohorts, rs6461378 associated with histologic NAFLD and with NAFLD-related metabolic traits including increased serum fatty acids, type 2 diabetes, hypertension, cardiovascular disease, and decreased HDL. SUN1 H118Y was subject to increased proteasomal degradation relative to wild-type SUN1 in cells, and SUN1 H118Y-expressing cells exhibited insulin resistance and increased lipid accumulation.
Collectively, these data support a potential causal role for the common SUN1 variant rs6461378 in NAFLD and metabolic disease.
Non-alcoholic fatty liver disease (NAFLD), with an estimated global prevalence of nearly 30%, is a growing cause of morbidity and mortality for which there is no approved pharmacologic therapy. Our data provide a rationale for broadening current concepts of NAFLD genetics and pathophysiology to include the nuclear envelope, and particularly Sad1 and UNC84 domain containing 1 (SUN1), as novel contributors to this common liver disease. Furthermore, if future studies confirm causality of the common SUN1 H118Y variant, it has the potential to become a broadly relevant therapeutic target in NAFLD and metabolic disease.
非酒精性脂肪性肝病（NAFLD）及其进行性形式——脂肪性肝炎（NASH）是一种遗传和表型上具有多样性的疾病，目前尚无获批的治疗方法，因此必须明确导致其发病机制的各种途径。核包膜蛋白编码基因中的罕见变异可导致早发性 NAFLD/NASH 伴脂肪营养不良；我们假设核包膜相关基因中的常见变异也可能导致肝脂肪变性和 NAFLD。
我们以肝脂肪变性为感兴趣的表型，对三个大型发现队列（>120000 名参与者）中的核包膜相关编码变异进行了关联荟萃分析，随后在大型验证队列（>600000 名参与者）中进行了表型关联研究，并在细胞培养中对与脂肪变性关联最强的变异进行了功能测试。
常见的蛋白编码变异 rs6461378（SUN1 H118Y）是我们关联荟萃分析中与脂肪变性关联最强的变异（p<0.001）。在不同祖先的验证队列中，rs6461378 与组织学 NAFLD 以及与 NAFLD 相关的代谢特征相关，包括血清脂肪酸增加、2 型糖尿病、高血压、心血管疾病和高密度脂蛋白降低。与野生型 SUN1 相比，SUN1 H118Y 更容易被蛋白酶体降解，表达 SUN1 H118Y 的细胞表现出胰岛素抵抗和脂质积累增加。
综上所述，这些数据支持常见的 SUN1 变异 rs6461378 在 NAFLD 和代谢疾病中可能具有因果作用。
非酒精性脂肪性肝病（NAFLD）的全球患病率估计接近 30%，是发病率和死亡率不断上升的原因，目前尚无批准的药物治疗方法。我们的数据为拓宽当前的 NAFLD 遗传学和病理生理学概念提供了依据，将核包膜，特别是 Sad1 和 UNC84 结构域包含蛋白 1（SUN1），作为这种常见肝病的新的贡献者。此外，如果未来的研究证实常见的 SUN1 H118Y 变异具有因果关系，它有可能成为 NAFLD 和代谢疾病中一个具有广泛相关性的治疗靶点。
