Effect of dietary eicosapentaenoic and docosahexaenoic acid on expression of rat liver genes controlling cholesterol homeostasis and on plasma cholesterol level

A hypothesis that eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) lower plasma cholesterol via increased expression of the Insig-1 gene with ensuing decrease of expression of genes coding for 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr) and low density lipoprotein receptor (Ldlr) was tested in rats fed a diet with 3% of fish oil (FO). Expression of the Insig-1 gene in the liver of the FO-fed rats was 730% (P < 0.05) of the control. However, contrary to the hypothesis, expression of the Hmgcr gene and Ldlr gene was 165% and 210% of the control (P > 0.05). Nevertheless, FO in the diet decreased (P < 0.05) plasma cholesterol of rats by 10% (from 1.19 to 1.07 mmol/l); it was therefore concluded that the cholesterol-lowering effect of EPA+DHA is at least partly based on mechanisms other than tested in the present experiment.  

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Long-term reversal of hypercholesterolemia in low density lipoprotein receptor (LDLR)-deficient mice by adenovirus-mediated LDLR gene transfer combined with CD154 blockade

The Journal of Gene Medicine ◽

10.1002/(sici)1521-2254(200001/02)2:1<41::aid-jgm79>3.0.co;2-p ◽

2000 ◽

Vol 2 (1) ◽

pp. 41-51 ◽

Cited By ~ 11

Author(s):

Colleen S. Stein ◽

In�s Martins ◽

Beverly L. Davidson

Keyword(s):

Gene Transfer ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Ldlr Gene ◽

Low Density Lipoprotein Receptor ◽

Density Lipoprotein Receptor ◽

Deficient Mice

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Bile Acids: The Good, the Bad, and the Ugly

Physiology ◽

10.1152/physiologyonline.1999.14.1.24 ◽

1999 ◽

Vol 14 (1) ◽

pp. 24-29 ◽

Cited By ~ 48

Author(s):

Alan F. Hofmann

Keyword(s):

Bile Acids ◽

Enterohepatic Circulation ◽

Cholesterol Metabolism ◽

Plasma Cholesterol ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipid Absorption ◽

Bile Acid Metabolism ◽

Cholesterol Levels ◽

Density Lipoprotein Receptor

Bile acids, amphipathic end products of cholesterol metabolism, are “good” in the infant because they enhance lipid absorption and thereby promote growth. Bile acids also induce bile flow and biliary lipid secretion. The enterohepatic circulation of bile acids is “bad” in the adult because it downregulates hepatocyte low-density lipoprotein receptor activity and thereby elevates plasma cholesterol levels. Defects in bile acid metabolism such as impaired biosynthesis or transport are “ugly” because they cause morbidity and death. New approaches for treating these defects are being developed.

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Modulation of hepatic apolipoprotein B, 3-hydroxy-3-methylglutaryl-CoA reductase and low-density lipoprotein receptor mRNA and plasma lipoprotein concentrations by defined dietary fats. Comparison of trimyristin, tripalmitin, tristearin and triolein

Biochemical Journal ◽

10.1042/bj3110167 ◽

1995 ◽

Vol 311 (1) ◽

pp. 167-173 ◽

Cited By ~ 31

Author(s):

A J Bennett ◽

M A Billett ◽

A M Salter ◽

E H Mangiapane ◽

J S Bruce ◽

...

Keyword(s):

Fatty Acids ◽

Plasma Lipids ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Dietary Fats ◽

Low Density ◽

Mrna Levels ◽

Expression Of Genes ◽

Coa Reductase

Different dietary fatty acids exert specific effects on plasma lipids but the mechanism by which this occurs is unknown. Hamsters were fed on low-cholesterol diets containing triacylglycerols enriched in specific saturated fatty acids, and effects on plasma lipids and the expression of genes involved in hepatic lipoprotein metabolism were measured. Trimyristin and tripalmitin caused significant rises in low-density lipoprotein (LDL) cholesterol which were accompanied by significant reductions in hepatic LDL receptor mRNA levels. Tripalmitin also increased hepatic expression of the apolipoprotein B gene, implying an increased production of LDL via very-low-density lipoprotein (VLDL) and decreased removal of LDL in animals fed this fat. Hepatic levels of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA did not vary significantly between the groups. Compared with triolein, tristearin had little effect on hepatic gene expression or total plasma cholesterol. However, it caused a marked decrease in VLDL cholesterol and a rise in LDL cholesterol such that overall it appeared to be neutral. Lipid analysis suggested a rapid desaturation of much of the dietary stearate. The differential changes in plasma lipids and hepatic mRNA levels induced by specific dietary fats suggests a role for fatty acids or a metabolite thereof in the regulation of the expression of genes involved in lipoprotein metabolism.

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Human Granulocyte-Macrophage Colony-Stimulating Factor Lowers the Levels of Plasma Cholesterol with an Increase in mRNA for Very Low Density Lipoprotein Receptor in Rabbitsa

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1994.tb17377.x ◽

2006 ◽

Vol 748 (1) ◽

pp. 630-633 ◽

Cited By ~ 4

Author(s):

T. ISHIBASHI ◽

K. YOKOYAMA ◽

J. SHINDO ◽

Y. HAMAZAKI ◽

Y. ENDO ◽

...

Keyword(s):

Plasma Cholesterol ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Very Low Density Lipoprotein ◽

Lipoprotein Receptor ◽

Colony Stimulating Factor ◽

Density Lipoprotein Receptor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Lunasin Improves the LDL-C Lowering Efficacy of Simvastatin via Inhibiting PCSK9 Expression in Hepatocytes and ApoE−/− Mice

Molecules ◽

10.3390/molecules24224140 ◽

2019 ◽

Vol 24 (22) ◽

pp. 4140 ◽

Cited By ~ 1

Author(s):

Lili Gu ◽

Yaqin Gong ◽

Cheng Zhao ◽

Yue Wang ◽

Qinghua Tian ◽

...

Keyword(s):

Combined Therapy ◽

Low Density Lipoprotein ◽

Plasma Concentrations ◽

Density Lipoprotein ◽

Low Density ◽

Therapeutic Drugs ◽

Density Lipoprotein Receptor ◽

Ldl Uptake ◽

Hepatocyte Nuclear Factor 1Α ◽

Coa Reductase

Statins are the most popular therapeutic drugs to lower plasma low density lipoprotein cholesterol (LDL-C) synthesis by competitively inhibiting hydroxyl-3-methyl-glutaryl-CoA (HMG-CoA) reductase and up-regulating the hepatic low density lipoprotein receptor (LDLR). However, the concomitant up-regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) by statin attenuates its cholesterol lowering efficacy. Lunasin, a soybean derived 43-amino acid polypeptide, has been previously shown to functionally enhance LDL uptake via down-regulating PCSK9 and up-regulating LDLR in hepatocytes and mice. Herein, we investigated the LDL-C lowering efficacy of simvastatin combined with lunasin. In HepG2 cells, after co-treatment with 1 μM simvastatin and 5 μM lunasin for 24 h, the up-regulation of PCSK9 by simvastatin was effectively counteracted by lunasin via down-regulating hepatocyte nuclear factor 1α (HNF-1α), and the functional LDL uptake was additively enhanced. Additionally, after combined therapy with simvastatin and lunasin for four weeks, ApoE−/− mice had significantly lower PCSK9 and higher LDLR levels in hepatic tissues and remarkably reduced plasma concentrations of total cholesterol (TC) and LDL-C, as compared to each monotherapy. Conclusively, lunasin significantly improved the LDL-C lowering efficacy of simvastatin by counteracting simvastatin induced elevation of PCSK9 in hepatocytes and ApoE−/− mice. Simvastatin combined with lunasin could be a novel regimen for hypercholesterolemia treatment.

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