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Isoflavones and phytosterols contained in Xuezhikang capsules modulate cholesterol homeostasis in high-fat diet mice.

Feng D, Sun JG, Sun RB, Ou-Yang BC, Yao L, Aa JY, Zhou F, Zhang JW, Zhang J, Wang GJ - Acta Pharmacol. Sin. (2015)

Bottom Line: Administration of F3 decreased serum TC, TG and LDL-C levels by 33%, 29% and 39%, respectively, and increased serum HDL-C by 28%, significantly reduced intestinal absorption of cholesterol by inhibiting the transcription of NPC1L1, and elevated excretion of TC, FC and CE by 96%, 72% and 101%, respectively.Administration of F2 showed pharmacological effects similar to those of lovastatin.Isoflavones and phytosterols act in a complimentary manner: through enhancing the elimination of bile acids and reducing intestinal cholesterol absorption, respectively.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

ABSTRACT

Aim: Xuezhikang (XZK), an extract of red yeast rice, has been widely used in traditional Chinese medicine to treat cardiovascular disease. Three fractions F1, F2 and F3 (primarily containing isoflavones, monacolins or phytosterols, respectively) are extracted from Xuezhikang capsules. In this study we evaluated the lipid-lowering effects of these fractions and explored the potential mechanisms of actions.

Methods: Mice treated with a high-fat diet (HFD) were orally administered lovastatin (10 mg·kg(-1)·d(-1)), XZK (1200 mg·kg(-1)·d(-1)), F1 (27.5 mg·kg(-1)·d(-1)), F2 (11.3 mg·kg(-1)·d(-1)) or F3 (35 mg·kg(-1)·d(-1)) for 10 weeks. Lipids were measured using commercial enzymatic kits, and the mRNA and protein levels of genes involved in cholesterol and bile acid homeostasis were evaluated using qRT-PCR and Western blot analysis, respectively.

Results: XZK increased the fecal excretion of lipids and bile acids, reduced serum TC, TG and LDL-C levels by 40%, 55% and 46%, respectively, and increased serum HDL-C by 31%. Administration of F1 repressed serum TC and TG by 24% and 52%, respectively, and elevated hepatic synthesis of CYP7A1. It also increased hepatic elimination of bile acids in the fecal excretions by 79% through upregulating BSEP and downregulating NTCP. Administration of F3 decreased serum TC, TG and LDL-C levels by 33%, 29% and 39%, respectively, and increased serum HDL-C by 28%, significantly reduced intestinal absorption of cholesterol by inhibiting the transcription of NPC1L1, and elevated excretion of TC, FC and CE by 96%, 72% and 101%, respectively. Administration of F2 showed pharmacological effects similar to those of lovastatin.

Conclusion: Isoflavones and phytosterols in XZK exert cholesterol-lowering effects in HFD mice through mechanisms that differ from those of lovastatin. Isoflavones and phytosterols act in a complimentary manner: through enhancing the elimination of bile acids and reducing intestinal cholesterol absorption, respectively.

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Related in: MedlinePlus

Mechanisms of the lipid-lowering effects of Xuezhikang (XZK) and F1 (isoflavones), F2 (monacolins), or F3 (sterols).
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fig8: Mechanisms of the lipid-lowering effects of Xuezhikang (XZK) and F1 (isoflavones), F2 (monacolins), or F3 (sterols).

Mentions: The mechanism of XZK action and the contribution of each of the three fractions to lowering cholesterol levels were further explored (Figures 5,6,7). XZK and F1 increased the reverse transport of excess cholesterol from the periphery to the liver by up-regulating hepatic SR-BI. XZK and F3 reduced intestinal absorption of exogenous cholesterol from foods by significantly inhibiting the transcriptional level of NPC1L1. XZK and F1 increased levels of bile acid synthase (CYP7A1) leading to increased conversion of cholesterol to bile acids. XZK and F1 augmented BA biliary secretion by increasing hepatic BSEP and repressing BA reabsorption by reducing NTCP. These results collectively demonstrate that XZK regulates cholesterol-bile acids homeostasis, reduces lipid absorption, and increases lipid excretion, thereby contributing to lower serum and hepatic lipid concentrations. F1 decreased the hepatic concentration and increased the fecal concentration of BA. F3 decreased hepatic lipids, while simultaneously increasing the excretion of fecal lipids. A similar effect by plant sterols has also been reported41,42,43,44,45. Our results reveal that F1 and F3 contribute to the cholesterol-lowering effect of XZK mainly by regulating bile acid and cholesterol homeostasis, respectively (Figure 8).


Isoflavones and phytosterols contained in Xuezhikang capsules modulate cholesterol homeostasis in high-fat diet mice.

Feng D, Sun JG, Sun RB, Ou-Yang BC, Yao L, Aa JY, Zhou F, Zhang JW, Zhang J, Wang GJ - Acta Pharmacol. Sin. (2015)

Mechanisms of the lipid-lowering effects of Xuezhikang (XZK) and F1 (isoflavones), F2 (monacolins), or F3 (sterols).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4816241&req=5

fig8: Mechanisms of the lipid-lowering effects of Xuezhikang (XZK) and F1 (isoflavones), F2 (monacolins), or F3 (sterols).
Mentions: The mechanism of XZK action and the contribution of each of the three fractions to lowering cholesterol levels were further explored (Figures 5,6,7). XZK and F1 increased the reverse transport of excess cholesterol from the periphery to the liver by up-regulating hepatic SR-BI. XZK and F3 reduced intestinal absorption of exogenous cholesterol from foods by significantly inhibiting the transcriptional level of NPC1L1. XZK and F1 increased levels of bile acid synthase (CYP7A1) leading to increased conversion of cholesterol to bile acids. XZK and F1 augmented BA biliary secretion by increasing hepatic BSEP and repressing BA reabsorption by reducing NTCP. These results collectively demonstrate that XZK regulates cholesterol-bile acids homeostasis, reduces lipid absorption, and increases lipid excretion, thereby contributing to lower serum and hepatic lipid concentrations. F1 decreased the hepatic concentration and increased the fecal concentration of BA. F3 decreased hepatic lipids, while simultaneously increasing the excretion of fecal lipids. A similar effect by plant sterols has also been reported41,42,43,44,45. Our results reveal that F1 and F3 contribute to the cholesterol-lowering effect of XZK mainly by regulating bile acid and cholesterol homeostasis, respectively (Figure 8).

Bottom Line: Administration of F3 decreased serum TC, TG and LDL-C levels by 33%, 29% and 39%, respectively, and increased serum HDL-C by 28%, significantly reduced intestinal absorption of cholesterol by inhibiting the transcription of NPC1L1, and elevated excretion of TC, FC and CE by 96%, 72% and 101%, respectively.Administration of F2 showed pharmacological effects similar to those of lovastatin.Isoflavones and phytosterols act in a complimentary manner: through enhancing the elimination of bile acids and reducing intestinal cholesterol absorption, respectively.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

ABSTRACT

Aim: Xuezhikang (XZK), an extract of red yeast rice, has been widely used in traditional Chinese medicine to treat cardiovascular disease. Three fractions F1, F2 and F3 (primarily containing isoflavones, monacolins or phytosterols, respectively) are extracted from Xuezhikang capsules. In this study we evaluated the lipid-lowering effects of these fractions and explored the potential mechanisms of actions.

Methods: Mice treated with a high-fat diet (HFD) were orally administered lovastatin (10 mg·kg(-1)·d(-1)), XZK (1200 mg·kg(-1)·d(-1)), F1 (27.5 mg·kg(-1)·d(-1)), F2 (11.3 mg·kg(-1)·d(-1)) or F3 (35 mg·kg(-1)·d(-1)) for 10 weeks. Lipids were measured using commercial enzymatic kits, and the mRNA and protein levels of genes involved in cholesterol and bile acid homeostasis were evaluated using qRT-PCR and Western blot analysis, respectively.

Results: XZK increased the fecal excretion of lipids and bile acids, reduced serum TC, TG and LDL-C levels by 40%, 55% and 46%, respectively, and increased serum HDL-C by 31%. Administration of F1 repressed serum TC and TG by 24% and 52%, respectively, and elevated hepatic synthesis of CYP7A1. It also increased hepatic elimination of bile acids in the fecal excretions by 79% through upregulating BSEP and downregulating NTCP. Administration of F3 decreased serum TC, TG and LDL-C levels by 33%, 29% and 39%, respectively, and increased serum HDL-C by 28%, significantly reduced intestinal absorption of cholesterol by inhibiting the transcription of NPC1L1, and elevated excretion of TC, FC and CE by 96%, 72% and 101%, respectively. Administration of F2 showed pharmacological effects similar to those of lovastatin.

Conclusion: Isoflavones and phytosterols in XZK exert cholesterol-lowering effects in HFD mice through mechanisms that differ from those of lovastatin. Isoflavones and phytosterols act in a complimentary manner: through enhancing the elimination of bile acids and reducing intestinal cholesterol absorption, respectively.

Show MeSH
Related in: MedlinePlus