This study aimed to evaluate the cholesterol-regulatory effects of lauric-acid-esterified octacosanol (LEO) and oleic-acid-esterified octacosanol (OEO) compared to their unmodified counterparts and to investigate the underlying mechanisms by partially substituting the fat content in obese C57BL/6J mice induced with a high-fat diet (HFD). Rice bran oil and coconut oil were also investigated as they are rich in oleic acid and lauric acid, respectively. The results showed that all supplemented groups significantly inhibited weight gain induced by the HFD, but the groups treated with esterified octacosanol exhibited a more pronounced effect. Esterified octacosanol inhibited fatty acid synthesis via the Sirtuin 1/AMP-activated protein kinase/Sterol regulatory element-binding protein 1 (SIRT1/AMPK/SREBP-1c) pathway by decreasing fatty acid synthase (FASN) (0.78 fold ±0.09, < 0.05) transcription and affecting the phospho-acetyl-coA carboxylase/acetyl-coA carboxylase (p-ACC/ACC) (1.42 fold ±0.18, < 0.05) ratio, as well as by inhibiting cholesterol synthesis by reducing sterol regulatory element-binding protein 2 (SREBP-2) (0.75 fold ±0.08, < 0.05) and low-density lipoprotein receptor (LDL-R) (1.24 fold ±0.1, < 0.05), which are responsible for cholesterol uptake. Our findings indicate that OEO had a greater influence on fatty acid and cholesterol synthesis compared to the other agents.
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