The value of surrogate markers to monitor cholesterol absorption, synthesis and bioconversion to bile acids under lipid lowering therapies

2017 ◽  
Vol 169 ◽  
pp. 111-122 ◽  
Author(s):  
Frans Stellaard ◽  
Klaus von Bergmann ◽  
Thomas Sudhop ◽  
Dieter Lütjohann
Keyword(s):  
Bile Acids ◽  
Cholesterol Absorption ◽  
Lipid Lowering ◽  
Surrogate Markers

Abstract 1927: High-dose Simvastatin Alone Inhibits Rho Kinase and Improves Flow-mediated Vasodilatation to a Greater Extent than Combination of Low-dose Simvastatin and Ezetimibe, Despite Comparable Lipid-Lowering

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ping-Yen Liu ◽  
Ping-Yen Liu ◽  
Yen-Wen Liu ◽  
Li-Jen Lin ◽  
Jyh-Hong Chen ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Low Dose ◽  
Cholesterol Biosynthesis ◽  
Rho Kinase ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Lipid Lowering ◽  
High Dose ◽  
Independent Effects ◽  
Rock Activity

Background: By inhibiting HMG-CoA reductase, statins not only inhibit cholesterol biosynthesis, but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho/Rho kinase (ROCK) pathway. In animal studies, inhibition of ROCK by statins improves endothelial function, decreases inflammation, and prevents atherosclerosis. These so-called cholesterol-independent effects of statins are dose-related and may contribute to some of their clinical benefits. We hypothesize that ezetimibe, which inhibits cholesterol absorption, does not exert these cholesterol-independent effects in humans. Methods and Results: We studied 60 dyslipidemia subjects (n=20 in each arm) in a prospective, randomized, observer-blinded study comparing treatment with simvastatin 40 mg/d or simvastatin/ezetimibe 10/10 mg/d to corresponding placebo tablets for 28 days. Prior statin usage was comparable between the groups and a washout period of 2 weeks was instituted before enrollment. Blood samples for fasting lipids, leukocyte ROCK activity and C-reactive protein (CRP) were collected at days 0 and 28. Baseline demographics, lipid levels, ROCK activity and CRP were not different between the 3 groups. Compared to placebo group, both treatment regimens decreased low-density lipoprotein cholesterol (LDL-C) by 38% and CRP by 32– 42% after 28 days (p<0.001 for both compared to placebo). Although LDL-C and CRP were reduced to comparable levels by either lipid-lowering regimen (p>0.05 between the groups), only simvastatin 40 mg reduced ROCK activity and improved forearm flow-mediated vasodilatation (FMD) (p<0.01 for both compared to baseline). The reduction of ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in LDL-C (p=0.01) and correlated with improvement in FMD (R 2 =0.78, p<0.01). However, there was no correlation between changes in FMD with changes in LDL-C or CRP. Conclusions: These findings suggest that despite comparable decrease in LDL-C and CRP, high-dose statin monotherapy has greater effects on both ROCK activity and endothelial function than low-dose statin and ezetimibe. These findings provide additional evidence of potential statin benefits beyond cholesterol lowering.

scholarly journals A metabolomic and pharmacokinetic study on the mechanism underlying the lipid-lowering effect of orally administered berberine

2015 ◽  
Vol 11 (2) ◽  
pp. 463-474 ◽  
Author(s):  
Shenghua Gu ◽  
Bei Cao ◽  
Runbin Sun ◽  
Yueqing Tang ◽  
Janice L. Paletta ◽  
...  
Keyword(s):  
Bile Acids ◽  
Pharmacokinetic Study ◽  
Lipid Lowering ◽  
Lowering Effect ◽  
Lipid Lowering Effect

The turnover of bile acids was involved in the lipid lowering effect of orally administered berberine.

scholarly journals Effect of Litholytic Bile Acids on Cholesterol Absorption in Gallstone Patients

1983 ◽  
Vol 84 (2) ◽  
pp. 265-271 ◽  
Author(s):  
Nicholas F. LaRusso ◽  
Johnson L. Thistle
Keyword(s):  
Bile Acids ◽  
Cholesterol Absorption

Effect of three different dihydroxy bile acids on intestinal cholesterol absorption in normal volunteers

1984 ◽  
Vol 87 (1) ◽  
pp. 144-149 ◽  
Author(s):  
Ottmar Leiss ◽  
Klaus von Bergmann ◽  
Ursula Streicher ◽  
Heribert Strotkoetter
Keyword(s):  
Bile Acids ◽  
Cholesterol Absorption ◽  
Intestinal Cholesterol Absorption ◽  
Normal Volunteers

scholarly journals Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome

2011 ◽  
Vol 107 (5) ◽  
pp. 705-711 ◽  
Author(s):  
Caroline Richard ◽  
Patrick Couture ◽  
Sophie Desroches ◽  
Suzanne Benjannet ◽  
Nabil G. Seidah ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Weight Loss ◽  
Body Weight ◽  
Control Diet ◽  
Cholesterol Absorption ◽  
Energy Restriction ◽  
Surrogate Markers ◽  
The Metabolic Syndrome ◽  
The Mediterranean ◽  
The Impact

The mechanisms implicated in the LDL-cholesterol (LDL-C)-lowering effects of the Mediterranean-type diet (MedDiet) are unknown. The present study assessed the impact of the MedDiet consumed under controlled feeding conditions, with and without weight loss, on surrogate markers of cholesterol absorption, synthesis and clearance using plasma phytosterols, lathosterol and proprotein convertase subtilisin/kexin-9 (PCSK9) concentrations, respectively, in men with the metabolic syndrome. The subjects' diet (n19, 24–62 years) was first standardised to a baseline North American control diet (5 weeks) followed by a MedDiet (5 weeks), both under weight-maintaining isoenergetic feeding conditions. The participants then underwent a 20-week free-living energy restriction period (10 (sd3) % reduction in body weight,P < 0·01), followed by the consumption of the MedDiet (5 weeks) under controlled isoenergetic feeding conditions. The LDL-C-lowering effect of the MedDiet in the absence of weight loss ( − 9·9 %) was accompanied by significant reductions in plasma PCSK9 concentrations ( − 11·7 %,P < 0·01) and in the phytosterol:cholesterol ratio ( − 9·7 %,P < 0·01) compared with the control diet. The addition of weight loss to the MedDiet had no further impact on plasma LDL-C concentrations and on these surrogate markers of LDL clearance and cholesterol absorption. The present results suggest that the MedDiet reduces plasma LDL-C concentrations primarily by increasing LDL clearance and reducing cholesterol absorption, with no synergistic effect of body weight loss in this process.

Molecular Insights into the Mechanisms Underlying the Cholesterol- Lowering Effects of Phytosterols

2019 ◽  
Vol 26 (37) ◽  
pp. 6704-6723 ◽  
Author(s):  
Lídia Cedó ◽  
Marta Farràs ◽  
Miriam Lee-Rueckert ◽  
Joan Carles Escolà-Gil
Keyword(s):  
Bile Acids ◽  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Plant Sterols ◽  
Intestinal Lumen ◽  
Low Density ◽  
Intestinal Cholesterol Absorption ◽  
Cholesterol Lowering

Dietary phytosterols, which comprise plant sterols and stanols, reduce plasma Low-Density Lipoprotein-Cholesterol (LDL-C) levels when given 2 g/day. Since this dose has not been reported to cause health-related side effects in long-term human studies, food products containing these plant compounds are used as potential therapeutic dietary options to reduce LDL-C and cardiovascular disease risk. Several mechanisms have been proposed to explain the cholesterol-lowering action of phytosterols. They may compete with dietary and biliary cholesterol for micellar solubilization in the intestinal lumen, impairing intestinal cholesterol absorption. Recent evidence indicates that phytosterols may also regulate other pathways. Impaired intestinal cholesterol absorption is usually associated with reduced cholesterol transport to the liver, which may reduce the incorporation of cholesterol into Very-Low- Density Lipoprotein (VLDL) particles, thereby lowering the rate of VLDL assembly and secretion. Impaired liver VLDL production may reduce the rate of LDL production. On the other hand, significant evidence supports a role for plant sterols in the Transintestinal Cholesterol Excretion (TICE) pathway, although the exact mechanisms by which they promote the flow of cholesterol from the blood to enterocytes and the intestinal lumen remains unknown. Dietary phytosterols may also alter the conversion of bile acids into secondary bile acids, and may lower the bile acid hydrophobic/hydrophilic ratio, thereby reducing intestinal cholesterol absorption. This article reviews the progress to date in research on the molecular mechanisms underlying the cholesterol-lowering effects of phytosterols.

Metabolic and genetic factors modulating subject specific LDL-C responses to plant sterol therapy1This article is an invited review for the Journal's Made In Canada section. The authors gratefully acknowledge the training that was acquired at the Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba. We would specifically like to thank Dr. Peter Jones for his mentorship and significant contribution to the research contained within this manuscript.

2012 ◽  
Vol 90 (5) ◽  
pp. 509-514 ◽  
Author(s):  
Todd C. Rideout ◽  
Scott V. Harding ◽  
Dylan S. Mackay
Keyword(s):  
Plant Sterol ◽  
Disease Risk ◽  
Current Knowledge ◽  
Cardiovascular Disease Risk ◽  
Cholesterol Absorption ◽  
Plant Sterols ◽  
Lipid Lowering ◽  
Clear Understanding ◽  
Significant Heterogeneity ◽  
Intestinal Cholesterol Absorption

Reducing intestinal cholesterol absorption with plant sterol consumption is a well-characterized strategy to lower LDL-C and potentially reduce cardiovascular disease risk. However, over 50 years of clinical research demonstrate that there is significant heterogeneity in the individual LDL-C lowering response to plant sterol therapy. A clear understanding of why plant sterols work effectively in some individuals but not in others will ensure optimal integration of plant sterols in future personalized nutritional lipid-lowering strategies. This review will examine the current knowledge base surrounding the metabolic and genetic determinants of LDL-C lowering in response to plant sterol consumption.

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