CM3-SII polysaccharide obtained from Cordyceps militaris ameliorates hyperlipidemia in heterozygous LDLR-deficient hamsters by modulating gut microbiota and NPC1L1 and PPARα levels

Accumulating evidence has demonstrated that polysaccharides derived from edible fungi have lipid-lowering effects in mice. However, the lipid metabolism mechanisms in mice and humans are different. We have previously elucidated the structural characteristics of the alkali-extracted polysaccharide CM3-SII obtained from Cordyceps militaris. This study aimed to investigate whether CM3-SII could ameliorate hyperlipidemia in a heterozygous low-density lipoprotein receptor (LDLR)-deficient hamster model of hyperlipidemia. Our data demonstrated that CM3-SII significantly decreased total plasma cholesterol, non-high-density lipoprotein cholesterol, and triglyceride levels in heterozygous LDLR-deficient hamsters. Unlike ezetimibe, CM3-SII could enhance the concentration of plasma apolipoprotein A1 and the expression of liver X receptor α/ATP-binding cassette transporter G8 mRNA pathway and suppress the expression of Niemann-Pick C1-like 1, which help to reduce cholesterol levels further. Moreover, the results of molecular docking analysis demonstrated that CM3-SII could directly bind to Niemann-Pick C1-like 1 with high affinity. The triglyceride-lowering mechanisms of CM3-SII were related to its downregulation of sterol regulatory element-binding protein 1c and upregulation of peroxisome proliferator-activated receptor α. Importantly, CM3-SII increased the abundance of Actinobacteria and Faecalibaculum and the ratio of Bacteroidetes/Firmicutes. Thus, CM3-SII attenuated hyperlipidemia by modulating the expression of multiple molecules involved in lipid metabolism and the gut microbiota. •The bioactive CM3-SII ameliorated hyperlipidemia in LDLR(+/−) hamsters.•It inhibited NPC1L1 and SREBP-1c, and enhanced PPARα in the liver.•It reduced the expression of NPC1L1 and enhanced LXRα/ABCG8 in gut.•It modulated the expression of PPARα, NPC1L1, and LXRα in cell models.•CM3-SII improves the relative abundance of gut microbiota.