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Diosgenin regulates cholesterol metabolism in hypercholesterolemic rats by inhibiting NPC1L1 and enhancing ABCG5 and ABCG8

Li, Ruoqi, Liu, Yi, Shi, Jingjing, Yu, Yantong, Lu, Haifei, Yu, Lu, Liu, Yanqiang, Zhang, Fengxia
Biochimica et biophysica acta 2019 v.1864 no.8 pp. 1124-1133
absorption, animal models, atherosclerosis, blood serum, body weight, cholesterol metabolism, diosgenin, excretion, fatty liver, high fat diet, homeostasis, hypercholesterolemia, intestines, liver, low density lipoprotein cholesterol, messenger RNA, protein synthesis, rats, risk factors, transporters, triacylglycerols
Hypercholesterolemia is a preventable risk factor for atherosclerosis and cardiovascular disease. However, the mechanisms of diosgenin (DG) that promote cholesterol homeostasis and alleviate hypercholesterolemia remain elusive. To investigate the effects and molecular mechanisms of the promotion of cholesterol metabolism by DG, a rat model of hypercholesterolemia was induced by providing a high-fat diet for 4 weeks. After 4 weeks, the rats were intragastrically administered high-dose DG (0.3 g/kg/d), low-dose DG (0.15 g/kg/d) or simvastatin (4 mg/kg/d) once a day for 8 weeks. The serum and hepatic cholesterol were tested, the mRNA and protein expression levels of Niemann-Pick C1-Like 1 (NPC1L1), liver X receptor-α (LXR-α) and the ATP-binding cassette G5/G8 (ABCG5/G8) transporters were measured. The results indicate that DG could reduce body weight, decrease the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, liver total cholesterol and free cholesterol levels compared to those in the controls. Simultaneously, liver tissue pathological morphology analyses revealed that DG could attenuate hepatic steatosis compared to that in the high-fat diet group. Further investigation demonstrated that DG significantly decreased the expression of NPC1L1 and LXR-α in the intestine and markedly increased the expression of ABCG5/G8 in the liver and intestine. Compared to the high-fat diet group, the rats in the DG-treated groups ameliorated hypercholesterolemia in a dose- and time-dependent manner. These data suggest that DG may not only inhibit intestinal cholesterol absorption by downregulating NPC1L1 but also enhance cholesterol excretion by increasing the expression of ABCG5/G8. DG could be a new candidate for the prevention of hypercholesterolemia.