The effect of long-chain n-3 PUFA on liver transcriptome in human obesity

•Almost 100 years after their discovery, n-3 PUFA continue to make an impact in addressing chronic diseases due to their anti-inflammatory and beneficial metabolic properties.•In this study n-3 PUFA mainly showed effects on immunity, cell signalling, metabolism, and inflammation.•Positive effects on insulin levels and the downregulation of glucagon suggest potential benefits for lipid metabolism.•No direct impact on insulin resistance was found at the gene expression level. Obesity is associated with a higher risk of severe diseases such as atherosclerotic cardiovascular disease, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). Polyunsaturated fatty acids, of the omega-3 family (n-3 PUFA), have been shown to reduce adipose tissue inflammation in obesity, as well as to have lipid-lowering effects and improve insulin sensitivity. However, direct effects on liver transcriptome in humans have not been described. Our aim was to understand the impact of n-3 PUFA on gene expression in obese human liver. Patients with obesity (BMI ≥ 40 kg/m2) were treated for eight weeks with 3.36 g n-3 PUFAs (1.84 g eicosapentaenoic acid (EPA) and 1.53 g docosahexaenoic acid (DHA)), or with 5 g of butter as a control (n = 15 per group) before undergoing bariatric surgery where liver biopsies were taken. Liver samples were used for mRNA microarray analyses and subsequently Gene Set Enrichment Analysis (GSEA) was performed. This bioinformatic approach led us to identify 80 significantly dysregulated pathways that were divided into 9 different clusters including insulin and lipid metabolism, and immunity. N-3 PUFA treatment significantly affected pathways related to immunity, metabolism, and inflammation. Specifically, it upregulated pathways involved in T-cell and B-cell functions and lipid metabolism, while downregulating glucagon signalling. These findings highlight the impact of n-3 PUFAs on key metabolic and immune processes in the liver of patients with obesity. This study provides further insights into the impact on n-3 PUFA on human liver gene expression, particularly in pathways associated with immunity, lipid metabolism, and inflammation, setting basis for further clinical research. Obesity increases the risk of diseases like atherosclerotic- cardiovascular disease, type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (MASLD). Omega-3 polyunsaturated fatty acids (n-3 PUFA) are known for