Qin Pan, Can-Jie Guo, Hai-Xia Cao, Rui-Dan Zheng, Yu-Qiang Mi, Rong Zhang, Feng Shen, Qing-Yang Xu
The A/A genotype at SIRT1 rs2394445 is associated with elevated serum TAGs containing saturated or monounsaturated fatty acids, which are linked to high-grade hepatic steatosis in MASLD independently of obesity.
AIMS: This exploratory study aimed to identify the effects of SIRT1 polymorphisms on the serum lipidomic profile and pathological characteristics in metabolic dysfunction-associated steatotic liver disease (MASLD).
MATERIALS: Chinese Han patients with biopsy-proven MASLD were genotyped for the single nucleotide polymorphisms (SNPs) in SIRT1. Lipidomics based on untargeted ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) was applied to map the SIRT1-driven serum lipid signature, followed by correlation analyses linking these lipid traits to hepatic steatosis, ballooning, lobular inflammation, and fibrosis. Integrative pathological scoring finally explored how SIRT1 variants that remodel circulating lipids may be associated with MASLD-specific histological change.
RESULTS: SIRT1 SNPs (rs3740053, rs2394443, rs2236318, rs7896005, rs2273773, rs2394445, and rs2394446) demonstrated extensive association with serum lipidomics of MASLD patients. SIRT1 rs2236318, rs7896005, and rs2394445, affecting 2, 7, and 7 serum triacylglycerols (TAGs) respectively, dominated the SIRT1 SNP-lipidomics association. Quantitative analysis revealed significantly elevated TAGs levels (48:0, 50:0, 50:1, 52:0, 52:1, 52:2, and 54:1), the most abundant species, in MASLD patients with rs2394445 A/A genotype compared with A/T+T/T. These elevated rs2394445-dependent TAG levels were associated with high-grade hepatic steatosis (rho: 0.367 to 0.540, p < 0.033-0.001) rather than ballooning, lobular inflammation, or fibrosis. The significant correlation of rs2394445 A/A genotype with severe steatosis suggested a potential pathological link through TAG profile modulation. In contrast, rs2394445 showed a limited effect on total circulating lipids and obesity indices (BMI, WHtR).
CONCLUSION: The A/A genotype at SIRT1 rs2394445 is associated with elevated serum TAGs containing saturated or monounsaturated fatty acids, which are linked to high-grade hepatic steatosis in MASLD independently of obesity.