Sesaminol alters phospholipid metabolism and alleviates obesity‐induced NAFLD

The prevalence of obesity‐induced non‐alcoholic fatty liver disease (NAFLD) and insulin resistance is increasing worldwide. We previously demonstrated that sesaminol increases thermogenesis in adipocytes, improves insulin sensitivity, and mitigates obesity in mice. In this study, we demonstrated that sesaminol increased mitochondrial activity and reduced ROS production in hepatocytes. Therefore, we delve into the metabolic action of sesaminol in obesity‐induced NAFLD or metabolic dysfunction‐associated liver disease (MAFLD). Here, we report that sesaminol induces OXPHOS proteins and mitochondrial function in vivo. Further, our data suggest that sesaminol administration reduces hepatic triacylglycerol accumulation and LDL‐C levels. Prominently, the lipidomics analyses revealed that sesaminol administration decreased the major phospholipids such as PC, PE, PI, CL, and PS to maintain membrane lipid homeostasis in the liver upon HFD challenge. Besides, SML reduced ePC and SM molecular species and increased PA levels in the HFD‐fed mice. Also, sesaminol renders anti‐inflammatory properties and dampens fibrosis markers in the liver. Remarkably, SML lowers the hepatic levels of ALT and AST enzymes and alleviates NAFLD in diet‐induced obese mice. The molecular docking analysis identifies peroxisome proliferator‐activated receptors as potential endogenous receptors for sesaminol. Together, our study demonstrates plant lignan sesaminol as a potential small molecule that alters the molecular species of major phospholipids, including sphingomyelin and ether‐linked PCs in the liver tissue, improves metabolic parameters, and alleviates obesity‐induced fatty liver disease in mice. The schematic model illustrates the action of sesaminol, a small molecule, in ameliorating obesity‐induced NAFLD by increasing mitochondrial activity and altering the lipidome of membrane lipids in high‐fat diet‐fed mice. Sesaminol combats obesity‐induced fatty liver disease by reducing hepatic LDL cholesterol, TG, ALT, and AST levels inflammation and fibrosis in the liver. Sesaminol shows a strong affinity and could act as a potential ligand for PPARγ, a nuclear receptor pivotal in regulating glucose and lipid homeostasis.