A common variant that alters SUN1 degradation associates with hepatic steatosis and metabolic traits in multiple cohorts

• Published in: Journal of hepatology Vol. 79; no. 5; pp. 1226 - 1235
• Main Authors: Upadhyay, Kapil K., Du, Xiaomeng, Chen, Yanhua, Buscher, Brandon, Chen, Vincent L., Oliveri, Antonino, Zhao, Raymond, Speliotes, Elizabeth K., Brady, Graham F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2023
• Subjects: autophagy; Diabetes Mellitus, Type 2; genetics; Humans; Insulin Resistance; laminopathy; Membrane Proteins - genetics; metabolic disease; Microtubule-Associated Proteins; Non-alcoholic Fatty Liver Disease - metabolism; nuclear envelope; Nuclear Proteins; Phenotype; proteasomal degradation; steatosis; genetics; autophagy; nuclear envelope; metabolic disease; steatosis; insulin resistance; proteasomal degradation; laminopathy
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2023.07.036

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. [Display omitted] •Association meta-analysis identified a strong positive association between a coding variant in SUN1 (rs6461378-T) and hepatic steatosis.•SUN1 variant positively associated with histologic NAFLD and NAFLD-related metabolic traits in separate validation cohorts.•This variant increased SUN1 degradation compared to the wild-type protein under nutrient-limited conditions (serum starvation).•The SUN1 variant increased lipid droplet accumulation and blunted insulin signaling in human hepatoma cell lines.