The Effects of Diosgenin on Hypolipidemia and Its Underlying Mechanism: A Review

Figures & data

Figure 1 The mechanism of diosgenin on lipid metabolism. As Figure 1 shows, the paper will elaborate the lipid metabolism regulating mechanism of diosgenin in detail. It includes diosgenin’s effects on inhibiting intestinal absorption of lipids, regulation of cholesterol transport, promoting cholesterol conversion into bile acid and excretion, inhibiting the endogenous lipid biosynthesis, effect on antioxidation, regulating lipoprotein lipase activity, and regulating transcription factors related to lipid metabolism.

Figure 2 Chemical structure of diosgenin. Its molecular formula is C₂₇H₄₂O₃, density is 1.1±0.1g/cm³, and relative molecular mass is 414.63.

Table 1 The Effect of Diosgenin on Markers Relevant to Lipid Metabolism

Model	Diosgenin Dose	Duration	Effects on the Plasma Lipid Profile and Transcription Factors	Pharmacological Effect	Reference
HFD^A Male SD^B rats	Protodioscin (0.5 mg/kg/d); intraperitoneal injection	15–28 days	TC↓,LDL↓,HDL↓,HDL/LDL↑	Inhibited HMG-CoA reductase on endoplasmic reticulum	[^Citation37]
HFD SPF^C Male SD rats	0.15, 0.3 g/kg/d; intragastrically	4 or 8 weeks	FTC↓,TTC↓, TC↓, TG↓, LDL-C↓ NPC1L1↓, ABCG5↑, ABCG8↑, LXR-α↓	Ameliorated hepatic steatosis and decreased the villi height and tunica mucosa thickness; Reduced cholesterol absorption; Increased cholesterol excretion	[^Citation21]
HCD^D Male Wistar rats	0.5g/100g orally	4 weeks	TC↓, TG↓, HDL-C↑, LDL-C↓	Reduced Cholesterol absorption in the intestine and/or increased Cholesterol excretion from the liver; Increased bile acid and Cholesterol excretions	[^Citation44]
STZ^E Male Wistar rats	40 mg/kg b.w. orally	45 days	TC↓, TG↓, Phospholipids↓, FFA↓, HMGR↓	Decreased cholesterol synthesis	[^Citation52]
HFD+ STZ Male SD rats	40, 80 mg/kg b.w. orally	14 days	TC↓, TG↓, SOD↑, GPX↑, GSH↑, TBARS↓, PPARγ↑, PPARα↑	Promoted pre-adipocytes differentiate; Antioxidation modulating oxidative stress	[^Citation68]
HFD Male SD rats	22.1, 44.2, 88.4 mg/kg/d orally	6 weeks	TC↓, TG↓,LDL-C↓, GSH-PX↑, NOS ↑, MDA↓, SOD↑, LPL↑, HL↑	Antioxidation and modulating oxidative stress; Attenuated H2O2-induced cytotoxicity and increased the cell viability; Accelerated lipids metabolism; Decreased cholesterol absorption and increased biliary cholesterol secretion;	[^Citation74]
HFD Male C57 mice	In drinking water, 5 mg/L every 2 days	4 weeks	PPARγ1↓, PPARγ2↓, Mest^F↓, MCP-1^G↓, IL-6↓, ROS↓	Ameliorated metabolic dysfunction; Inhibited adipocyte differentiation	[^Citation97]
Gestational diabetes-induced C57BL/KsJ^+/+(wild type, homozygous) and C57BL/KsJ^db/+(db/+, heterozygous) mice	Protocol 1: 10, 20 mg/kg b.w; Protocol 2: 20mg/kg intragastric tube	4 weeks	TBARS↓, SOD↑, CAT↑, GSH↑, TC↓, TG↓, LDL↓, SREBP-1↓, FAS↓, SCD-1↓, ACC↓	Antioxidation and regulation of oxidative stress; Inhibited the mRNA induction of lipogenic genes	[^Citation86]
HCD Male SD rats	0.1%, 0.5% diet orally	6 weeks	ALT↓, AST↓, TC↓, HDL-C↑, HDL/TC↑, GSH-Px↑, SOD↑, TBARS↓	Liver protective effect; Antioxidation and regulation of oxidative stress; protection against lymphocyte DNA damage in both unstressed and stressed cells; Inhibited pancreatic lipase activity	[^Citation71]
HFD Male KK-Ay/Ta Jcl mice (obese diabetic model)	0.5%, 2.0% fenugreek orally	4 weeks	TG↓, SREBP-1↓, FAS↓, SCD-1↓, ACC↓, LXR↓	Inhibited the mRNA induction of lipogenic genes; Inhibited hepatic steatosis	[^Citation53]
HFD KK-Ay/Ta Jcl mice (obese diabetic model)	0.5%, 2% fenugreek orally	4 weeks	aP2↑, LPL↑, Glut4↑, PPARγ1↑, MCP-1↓, TNF-α↓, adiponectin↑	Enhanced insulin sensitivity; Promoted adipocyte differentiation and inhibited obesity-related inflammation	[^Citation72]
HCD Male New Zealand White rabbits	50 g/kg 50 mesh-size, 50 g/kg nanoscale Dioscorea pseudojaponica orally	8 weeks	TC↓, TG↓, AMPK↑, ACC↑	Prevented lipid accumulation within liver tissue; Accelerated lipid catabolism	[^Citation54]
Semipurified-diet + 0.1% cholesterol female cynomolgus macaques	1% die orally	3 weeks	TC↓, TG↓,	Increased cholesterol excretion	[^Citation38]
Male apoE KO mice	1% (w/w) orally	8 weeks	TC↓, FC↓, CE↓, ABCA1↑, miR-19b ↓	Enhanced macrophage cholesterol efflux; Inhibited macrophage cholesterol accumulation; accelerated RCT and improves plasma lipid profile; Inhibited aortic lipid deposition and atherogenesis	[^Citation63]
HFD Male SD rats	0.5%, 1% (w/w) orally	16 weeks	HDL↑, LDL↓, TG↓, ALT↓, pAMPK↑, pACC↑, AMPK↑, ACC↑,SREBP1-c↓, LXRα↓	Increased AMPK and ACC phosphorylation; accelerated lipid catabolism	[^Citation91]
45% kcal-fat content male Wistar rats	20, 40, 80 mg/kg for mice and 15, 30, 60 mg/kg for rats orally	8 weeks	AST↓,ALT↓,TG↓,TC↓,FFA↓,SREBP-1c↓,CPT↑,FAS↓,SCD↓,FoxO1↑,ATGL↑,SOD↑,MDA↓,GSH↑,SIRT1↑	Improved hepatic lipid metabolism; decreased triacylglycerol accumulation	[^Citation87]
HepG2 cells; THP-1 monocytic cells	Protodioscin, pseudoprotodioscin, methylprotodioscin(5μm, 10μm, 25μm)	24h; 48h	ABCA1↑, SREBP-1↓, SREBP-2↓, LXRα↓,PCSK9↓,FAS↓,ACC↓, LDLR↑	Inhibited cholesterol triglycerides synthesis; accelerated RCT and improved plasma lipid profile;	[^Citation64]
Human THP-1 monocytic cells; HepG2 cells	Methyl protodioscin(100μm)	24h	SREBP1c↓,SREBP2↓,miR-33a/b↓, ABCA1↑,HMGCR↑,FAS↓, ACC↓, LXRα↓	Inhibited cholesterol triglycerides synthesis	[^Citation45]
C57BL/6 male mice; Wistar male rats	Acute experiment: 28, 56, 84 mg/kg/d; chronic test: 20, 40, 60mg/kg/d; intragastrically	Acute experiment: 2 weeks; chronic test: 12 weeks	AST↓,ALT↓,TG↓,TC↓,SOD↑,MDA↓,GSH↑,GSH-Px↑, GSR↑,TnF-α↓,IL-6↓, p38↓,pERK↓, pJNK↓,CYP2E1↓,PPARα↑,CPT↑,MCAD↑	Reduced the oxidative stress,Inflammatory cytokine production, apoptosis and liver steatosis	[^Citation70]
HFD C57BL/6J male mice	50, 100 dioscin mg/kg/d intragastrically	7 weeks	SREBP-1c↓, FAS↓, GLUT4↓, pAMPK↑, pACC↑, p38↓, pERK↓	Inhibited cholesterol triglycerides synthesis; Increased AMPK and ACC phosphorylation;	[^Citation57]
SW480 cell	6.21 μg/mL	24h; 48h	ACC↓,FAS↓,PPARγ↑, LDLR↑	Inhibited the mRNA induction of lipogenic genes; decreased cholesterol absorption	[^Citation88]
HFD Male SD rats	150, 300 mg/kg/d, intragastrically	8 weeks	TC↓, TG↓, LDL-C↓, HDL-C↑, SRB1↑, CES-1↑, CYP7A1↑, FXR↓	Accelerated hepatic RCT; enhanced cholesterol elimination	[^Citation49]
	1% (1g/100g)

Abbreviations: ^AHFD, High-fat diet-fed; ^BSD, Sprague–Dawley; ^CSPF, specific-pathogen-free; ^DHCD, high-cholesterol diet; ^ESTZ, Streptozotocin-Induced; ^FMest, mesoderm specific transcript; ^GMCP-1, monocyte chemoattractant protein.

Figure 3 Schematic representation of molecular mechanisms of diosgenin attenuates cholesterol metabolism. As shown in the figure, diosgenin can inhibit cholesterol intake of human liver and intestinal cells mediated by NPC1L1. Diosgenin regulates lipid homeostasis by inhibiting the expression of a series of enzymes needed by SREBPs to affect endogenous cholesterol, fatty acid, triglyceride and phospholipid synthesis. LDLR is the transcriptional target of SREBP2, diosgenin can enhance LDLR mediated uptake of cholesterol by peripheral cells from the circulation. Notably, Diosgenin may also inhibit PCSK9 mediated lysosomal degradation of PCSK9-LDLR complex and avoid LDL accumulation in vivo. Diosgenin can promote ABCA1 mediated RCT process, promote cellular efflux of phospholipids and cholesterol to lipid-poor apolipoproteinA-1 (apoA-1) and removal of excess cholesterol. ABCG 5/G 8 is activated by diosgenin, which promotes the secretion of unesterified free cholesterol into the bile canaliculus or gut lumen for fecal excretion and prevents the accumulation of sterols in diet. In addition, CYP7A1 was activated by diosgenin to catalyze the conversion of accumulated cholesterol to primary bile acids in liver. At present, whether diosgenin can regulate cholesterol metabolism through LXRs is not very clear. (+) promotion, (–) inhibition.

Wang T , Choi RC , Li J , et al. Antihyperlipidemic effect of protodioscin, an active ingredient isolated from the rhizomes of Dioscorea nipponica. Planta Med . 2010;76(15):1642–1646. doi:10.1055/s-0030-1249960 20509104

 PubMed Web of Science ®Google Scholar

Li R , Liu Y , Shi J , et al. Diosgenin regulates cholesterol metabolism in hypercholesterolemic rats by inhibiting NPC1L1 and enhancing ABCG5 and ABCG8. Biochim Biophys Acta Mol Cell Biol Lipids . 2019;1864(8):1124–1133. doi:10.1016/j.bbalip.2019.04.010 31054325

 PubMed Web of Science ®Google Scholar

Kusano Y , Tsujihara N , Masui H , Kozai H , Takeuchi W . Consumption of Japanese yam improves lipid metabolism in high-cholesterol diet-fed rats. Nutr Sci Vitaminol (Tokyo) . 2016;62(5):350–360. doi:10.3177/jnsv.62.350

 Web of Science ®Google Scholar

Hao S , Xu R , Li D , Zhu Z , Wang T , Liu K . Attenuation of streptozotocin-induced lipid profile anomalies in the heart, brain, and mRNA expression of HMG-CoA reductase by diosgenin in rats. Cell Biochem Biophys . 2015;72(3):741–749. doi:10.1007/s12013-015-0525-8 25631375

 PubMed Web of Science ®Google Scholar

Sangeetha MK , ShriShri Mal N , Atmaja K , Sali VK , Vasanthi HR . PPAR’s and diosgenin a chemico biological insight in NIDDM. Chem Biol Interact . 2013;206(2):403–410. doi:10.1016/j.cbi.2013.08.014 24001619

 PubMed Web of Science ®Google Scholar

Gong G , Qin Y , Huang W , et al. Protective effects of diosgenin in the hyperlipidemic rat model and in human vascular endothelial cells against hydrogen peroxide-induced apoptosis. Chem Biol Interact . 2010;184(3):366–375. doi:10.1016/j.cbi.2010.02.005 20149787

 PubMed Web of Science ®Google Scholar

Wang X , Liu J , Long Z , et al. Effect of diosgenin on metabolic dysfunction: role of ERbeta in the regulation of PPARgamma. Toxicol Appl Pharmacol . 2015;289(2):286–296. doi:10.1016/j.taap.2015.09.015 26408789

 PubMed Web of Science ®Google Scholar

Hua S , Li Y , Su L , Liu X . Diosgenin ameliorates gestational diabetes through inhibition of sterol regulatory element-binding protein-1. Biomed Pharmacother . 2016;84:1460–1465. doi:10.1016/j.biopha.2016.10.049 27810341

 PubMed Web of Science ®Google Scholar

Son IS , Kim JH , Sohn HY , Son KH , Kim JS , Kwon CS . Antioxidative and hypolipidemic effects of diosgenin, a steroidal saponin of yam (Dioscorea spp.), on high-cholesterol fed rats. Biosci Biotechnol Biochem . 2007;71(12):3063–3071. doi:10.1271/bbb.70472 18071250

 PubMed Web of Science ®Google Scholar

Uemura T , Goto T , Kang MS , et al. Diosgenin, the main aglycon of fenugreek, inhibits LXRalpha activity in HepG2 cells and decreases plasma and hepatic triglycerides in obese diabetic mice. J Nutr . 2011;141(1):17–23. doi:10.3945/jn.110.125591 21106928

 PubMed Web of Science ®Google Scholar

Uemura T , Hirai S , Mizoguchi N , et al. Diosgenin present in fenugreek improves glucose metabolism by promoting adipocyte differentiation and inhibiting inflammation in adipose tissues. Mol Nutr Food Res . 2010;54(11):1596–1608. doi:10.1002/mnfr.200900609 20540147

 PubMed Web of Science ®Google Scholar

Pan CH , Tsai CH , Liu FC , et al. Influence of different particle processing on hypocholesterolemic and antiatherogenic activities of yam (Dioscorea pseudojaponica) in cholesterol-fed rabbit model. Sci Food Agric . 2013;93(6):1278–1283. doi:10.1002/jsfa.5882

 Web of Science ®Google Scholar

Malinow MR , Elliott WH , McLaughlin P , Upson B . Effects of synthetic glycosides on steroid balance in Macaca fascicularis. J Lipid Res . 1987;28(1):1–9. doi:10.1016/S0022-2275(20)38729-0 3559397

 PubMed Web of Science ®Google Scholar

Lv YC , Yang J , Yao F , et al. Diosgenin inhibits atherosclerosis via suppressing the MiR-19b-induced downregulation of ATP-binding cassette transporter A1. Atherosclerosis . 2015;240(1):80–89. doi:10.1016/j.atherosclerosis.2015.02.044 25765596

 PubMed Web of Science ®Google Scholar

Cheng S , Liang S , Liu Q , et al. Diosgenin prevents high-fat diet-induced rat non-alcoholic fatty liver disease through the AMPK and LXR signaling pathways. Int J Mol Med . 2018;41(2):1089–1095.29207101

 PubMed Web of Science ®Google Scholar

Yao H , Tao X , Xu L , et al. Dioscin alleviates non-alcoholic fatty liver disease through adjusting lipid metabolism via SIRT1/AMPK signaling pathway. Pharmacol Res . 2018;131:51–60. doi:10.1016/j.phrs.2018.03.017 29574225

 PubMed Web of Science ®Google Scholar

Gai Y , Li Y , Xu Z , Chen J . Pseudoprotodioscin inhibits SREBPs and microRNA 33a/b levels and reduces the gene expression regarding the synthesis of cholesterol and triglycerides. Fitoterapia . 2019;139:104393. doi:10.1016/j.fitote.2019.104393 31669721

 PubMed Web of Science ®Google Scholar

Ma W , Ding H , Gong X , et al. Methyl protodioscin increases ABCA1 expression and cholesterol efflux while inhibiting gene expressions for synthesis of cholesterol and triglycerides by suppressing SREBP transcription and microRNA 33a/b levels. Atherosclerosis . 2015;239(2):566–570. doi:10.1016/j.atherosclerosis.2015.02.034 25733328

 PubMed Web of Science ®Google Scholar

Xu T , Zheng L , Xu L , et al. Protective effects of dioscin against alcohol-induced liver injury. Arch Toxicol . 2014;88(3):739–753. doi:10.1007/s00204-013-1148-8 24146112

 PubMed Web of Science ®Google Scholar

Poudel B , Lim SW , Ki HH , Nepali S , Lee YM , Kim DK . Dioscin inhibits adipogenesis through the AMPK/MAPK pathway in 3T3-L1 cells and modulates fat accumulation in obese mice. Int J Mol Med . 2014;34(5):1401–1408. doi:10.3892/ijmm.2014.1921 25189808

 PubMed Web of Science ®Google Scholar

Mohammad-Sadeghipour M , Mahmoodi M , Noroozi Karimabad M , Mirzaei MR , Hajizadeh MR . Diosgenin and 4-hydroxyisoleucine from fenugreek are regulators of genes involved in lipid metabolism in the human colorectal cancer cell line SW480. Cell J . 2021;22(4):514–522.32347045

 PubMed Web of Science ®Google Scholar

Yu L , Lu H , Yang X , et al. Diosgenin alleviates hypercholesterolemia via SRB1/CES-1/CYP7A1/FXR pathway in high-fat diet-fed rats. Toxicol Appl Pharmacol . 2021;412:115388. doi:10.1016/j.taap.2020.115388 33383043

 PubMed Web of Science ®Google Scholar