Inhibition of cholesterol biosynthesis by Δ22-unsaturated phytosterols via competitive inhibition of sterol Δ24-reductase in mammalian cells (original) (raw)
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The Biochemical journal, 2002
Dietary phytosterols are cholesterol-lowering agents that interfere with the intestinal absorption of cholesterol. In the present study, we have studied their effects on cholesterol biosynthesis in human cells, particularly in the sterol-conversion pathway. For this, both Caco-2 (intestinal mucosa) and HL-60 (promyelocytic) human cell lines were incubated with [(14)C]acetate, and the incorporation of radioactivity into sterols was determined using HPLC and radioactivity detection online. Sterols containing a double bond at C-22 in the side chain (stigmasterol, brassicasterol and ergosterol) dramatically inhibited the activity of sterol Delta(24)-reductase, as indicated by the decrease in radioactivity incorporation into cholesterol and the accumulation of its precursors (mainly desmosterol). Phytosterols with the saturated side chain (beta-sitosterol and campesterol) were inactive in this regard. The inhibition of sterol (24)-reductase was confirmed in rat liver microsomes by using ...
New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism
Atherosclerosis, 2009
Plant sterols and stanols (phytosterols/phytostanols) are known to reduce serum low-density lipoprotein (LDL)-cholesterol level, and food products containing these plant compounds are widely used as a therapeutic dietary option to reduce plasma cholesterol and atherosclerotic risk. The cholesterol-lowering action of phytosterols/phytostanols is thought to occur, at least in part, through competition with dietary and biliary cholesterol for intestinal absorption in mixed micelles. However, recent evidence suggests that phytosterols/phytostanols may regulate proteins implicated in cholesterol metabolism both in enterocytes and hepatocytes. Important advances in the understanding of intestinal sterol absorption have provided potential molecular targets of phytosterols. An increased activity of ATP-binding cassette transporter A1 (ABCA1) and ABCG5/G8 heterodimer has been proposed as a mechanism underlying the hypocholesterolaemic effect of phytosterols. Conclusive studies using ABCA1 and ABCG5/G8-deficient mice have demonstrated that the phytosterol-mediated inhibition of intestinal cholesterol absorption is independent of these ATP-binding cassette (ABC) transporters. Other reports have proposed a phytosterol/phytostanol action on cholesterol esterification and lipoprotein assembly, cholesterol synthesis and apolipoprotein (apo) B100-containing lipoprotein removal. The accumulation of phytosterols in ABCG5/G8-deficient mice, which develop features of human sitosterolaemia, disrupts cholesterol homeostasis by affecting sterol regulatory element-binding protein (SREBP)-2 processing and liver X receptor (LXR) regulatory pathways. This article reviews the progress to date in studying these effects of phytosterols/phytostanols and the molecular mechanisms involved.
Plant sterols, cholesterol metabolism and related disorders
Plant sterols and stanols are known to reduce serum LDL-cholesterol levels, and food products containing these plant compounds are widely used as a therapeutic dietary option to reduce plasma cholesterol and atherosclerotic risk. The cholesterol-lowering action of plant sterols is thought to occur, at least in part, through competition with dietary and biliary cholesterol for intestinal absorption in mixed micelles. However, recent evidence suggests that plant sterols may regulate proteins inolved in cholesterol metabolism both in enterocytes and hepatocytes. Important advances in the understanding of intestinal sterol absorption have provided potential molecular targets of phytosterols. Nevertheless, conclusive studies using ABCA1 and ABCG5/G8- deficient mice have demonstrated that the phytosterol-mediated inhibition of intestinal cholesterol absorption is independent of these ABC transporters. Other reports have proposed a plant sterol action on cholesterol esterification and lipo...
Frontiers in Nutrition, 2022
Non-cholesterol sterols are transported in plasma lipoproteins and are consequently important in cholesterol metabolism. We investigated the distribution of non-cholesterol sterol precursors of cholesterol synthesis (NCSPCS), oxysterols, and phytosterols in lipoproteins of healthy subjects differing according to HDL-Cholesterol (HDL-C) plasma levels. Elevated NCSPCS (desmosterol, lathosterol) in the High HDL group suggests that HDL exports these sterols from cells, but not the cholesterol metabolite 24-OHC which was higher in the Low HDL group than in the High HDL group. 27-hydroxycholesterol (27OH-C) plasma levels did not differ between groups. Percentage of NCSPCS and phytosterols predominates in LDL, but did not differ between groups. Thirty percent of desmosterol and lathosterol are present in HDL, with the High HDL group carrying higher percentage of these sterols. A high percentage of campesterol and sitosterol in HDL suggests that phytosterols are absorbed by enterocytes, and...
Role of naturally-occurring plant sterols on intestinal cholesterol absorption and plasmatic levels
Journal of Physiology and Biochemistry, 2009
J Physiol Biochem, 65 (1), [87][88][89][90][91][92][93][94][95][96][97][98] 2009 T. SANCLEMENTE, I. MARQUES-LOPES, J. PUZO and A.L. GARCÍA-OTÍN. Role of naturally-occurring plant sterols on intestinal cholesterol absorption and plasmatic levels (minireview). J Physiol Biochem, 65 (1), [87][88][89][90][91][92][93][94][95][96][97][98] 2009. Cardiovascular disease is a major health problem in developed countries although its incidence is relatively lower in Mediterranean countries which is partly ascribed to dietary habits. Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (c-LDL), increases cardiovascular disease. Phytosterols are bioactive compounds, found in all vegetable foods, which inhibit intestinal cholesterol absorption and, therefore, have a serum cholesterollowering effect. Intestinal cholesterol absorption is a multistep process where plant sterols and stanols may act: a) attenuating the NPC1L1 gene expression, which may result in a lower cholesterol uptake from the lumen; b) lowering the cholesterol esterification rate by the ACAT2 (acyl-CoA cholesterol acyltransferase) and, consequently, the amount of cholesterol secreted via the chylomicrons and c) upregulating the expression of ABC-transporters ABCG5 and ABCG8 in intestinal cells, which may result in an increased excretion of cholesterol by the enterocyte back into the lumen. Many clinical trials proved that commercial products enriched with phytosterols reduce cholesterol levels. Likewise, recent studies show that phytosterols present in natural food matrices are also effective and could be an important component of cardioprotective dietary patterns such as the Mediterranean diet.
A Reappraisal of the Mechanism by Which Plant Sterols Promote Neutral Sterol Loss in Mice
PloS one, 2011
Dietary plant sterols (PS) reduce serum total and LDL-cholesterol in hyperlipidemic animal models and in humans. This hypocholesterolemic effect is generally ascribed to inhibition of cholesterol absorption. However, whether this effect fully explains the reported strong induction of neutral sterol excretion upon plant sterol feeding is not known. Recent data demonstrate that the intestine directly mediates plasma cholesterol excretion into feces, i.e., without involvement of the hepato-biliary route. Objective: Aim of this study was to determine whether stimulation of fecal neutral sterol loss during PS feeding is (partly) explained by increased intestinal cholesterol excretion and to assess the role of the cholesterol transporter Abcg5/Abcg8 herein. Methods and Results: Wild-type mice were fed a control diet or diets enriched with increasing amounts of PS (1%, 2%, 4% or 8%, wt/wt) for two weeks. In addition, Abcg5-/mice were fed either control or 8% PS diet. PS feeding resulted in a dosedependent decrease of fractional cholesterol absorption (,2-7-fold reduction) in wild-type mice and ,80% reduction in Abcg5-/mice. Furthermore, PS feeding led to a strong, dose-independent induction of neutral sterol excretion (3.4-fold in wild-types and 2.7-fold in Abcg5-/mice) without changes in biliary cholesterol secretion. It was calculated that PS feeding stimulated intestinal cholesterol excretion by ,500% in wild-type mice and by ,250% in Abcg5-/-. Conclusions: Our data indicate that in mice the cholesterol-lowering effects of PS are to a large extent attributable to stimulation of intestinal, non-bile derived, cholesterol excretion. The Abcg5/Abcg8 heterodimer is involved in facilitating this PS-induced flux of cholesterol.
Plant sterols for human health- A review
Journal of Applied and Natural Science
The aim of the article was to review phytosterols as functional food and its significance in lowering cholesterol as well as its specific effect on human health. Phytosterols has been known for its cholesterol lowering action long time back but the uprising of phytosterols in form of functional foods gained the interest once again. Fatty food matrix provides optimal solubility but fortification of phytosterols with other food matrices like low fat fermented milk, bread, juice are showing positive results. A dose of 2 g/day of either steryl or stanyl esters has been prescribed for an optimum effect which has been confirmed by FDA and EC. A number of studies have documented the safety and the efficiency of phytosterols. But there is still a big question mark on the use of it because of their adverse effect on body in form of Phytosterol oxidation products (POPs). It needs further investigation to elucidate effect of POPs within body.