Effects of limonin and nomilin on lipid metabolic homeostasis in hyperlipidemic mice

This study investigated the effects of different doses (5 mg mL^-1 and 10 mg mL^-1) of limonin and nomilin on the lipid metabolic homeostasis of high-fat diet-fed mice by oral gavage. The results showed that both limonin and nomilin interventions could significantly reduce the serum levels of TC, TG and LDL-C in high-fat diet-fed mice (<i>p</i> < 0.05), while greatly increased the level of HDL-C (<i>p</i> < 0.05), particularly with an increase of 71.95% after nomilin intervention at a high dose. In addition, the pathological damage of colonic adipose tissue improved after either limonin or nomilin intervention, and goblet cells increased by 17.19%-31.21% when compared with the HFD group. Limonin and nomilin interventions could improve the structure of the intestinal flora of hyperlipidemic mice, along with probiotics, <i>e.g.</i>, <i>Lachnospiraceae</i> increased and harmful bacteria, <i>e.g.</i>, <i>Helicobacter</i> and <i>Desulfovibrio</i>, abundance decreased significantly (<i>p</i> < 0.05). Metabolomic analysis revealed distinct metabolic remodeling effects, including the modulation of key metabolites involved in lipid metabolism and steroid hormone biosynthesis; notably, nomilin exhibited superior lipid-regulating efficacy compared to limonin, with specific upregulation of steroid hormone biosynthesis-related metabolites (<i>e.g.</i>, estrone glucuronide and estrone 3-sulfate). This study could advance our understanding of the therapeutic potential of citrus-derived limonoids in restoring lipid metabolic homeostasis and provides a mechanistic basis for their application in functional foods or nutraceuticals.