Non-Cholesterol Sterol Concentrations as Biomarkers for Cholesterol Absorption and Synthesis in Different Metabolic Disorders: A Systematic Review

Non-cholesterol sterols are validated biomarkers for intestinal cholesterol absorption and endogenous cholesterol synthesis. However, their use in metabolic disturbances has not been systematically explored. Therefore, we conducted a systematic review to provide an overview of non-cholesterol sterols as markers for cholesterol metabolism in different metabolic disorders. Potentially relevant studies were retrieved by a systematic search of three databases in July 2018 and ninety-four human studies were included. Cholesterol-standardized levels of campesterol, sitosterol and cholestanol were collected to reflect cholesterol absorption and those of lathosterol and desmosterol to reflect cholesterol synthesis. Their use as biomarkers was examined in the following metabolic disorders: overweight/obesity (n = 16), diabetes mellitus (n = 15), metabolic syndrome (n = 5), hyperlipidemia (n = 11), cardiovascular disease (n = 17), and diseases related to intestine (n = 16), liver (n = 22) or kidney (n = 2). In general, markers for cholesterol absorption and synthesis displayed reciprocal patterns, showing that cholesterol metabolism is tightly regulated by the interplay of intestinal absorption and endogenous synthesis. Distinctive patterns for cholesterol absorption or cholesterol synthesis could be identified, suggesting that metabolic disorders can be classified as ‘cholesterol absorbers or cholesterol synthesizers’. Future studies should be performed to confirm or refute these findings and to examine whether this information can be used for targeted (dietary) interventions.

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Plasma Non-cholesterol Sterols as Markers of Cholesterol Synthesis and Intestinal Absorption: A Critical Review

Current Pharmaceutical Design ◽

10.2174/1381612826666200730220230 ◽

2020 ◽

Vol 26 (40) ◽

pp. 5152-5162

Author(s):

Eder Carlos Rocha Quintão

Keyword(s):

Intestinal Absorption ◽

Cholesterol Synthesis ◽

Cholesterol Metabolism ◽

Plasma Concentrations ◽

Cholesterol Absorption ◽

Population Based ◽

Whole Body ◽

Intestinal Lumen ◽

Intestinal Cholesterol Absorption ◽

Artery Disease

Plasma concentrations of phytosterols and non-cholesterol sterol precursors of cholesterol synthesis have been used as markers of intestinal cholesterol absorption and synthesis in inherited and secondary dyslipidemias and in population-based investigations to evaluate the risk for cardiovascular disease, respectively. The method aims at replacing initial research procedures such as the use of stable isotopes associated with fecal steroid balance, which are limited by the high cost and tedious procedures. However, we show in this review that numerous results obtained with serum sterol measurements are contradictory. In this regard, the following points are discussed: 1) how phytosterols relate to atherosclerosis considering that defects in biliary output or in the transport of phytosterols from the intestinal mucosa back into the intestinal lumen provide increased content of phytosterols and other sterols in plasma and tissues, thus not allowing to conclude that their presence in arteries and atheromas represents the etiology of atherosclerosis; 2) serum non-cholesterol sterols as markers of cholesterol synthesis and absorption, such as cholestanol, present discrepant results, rendering them often inadequate to identify cases of coronary artery disease as well as alterations in the whole body cholesterol metabolism; 3) such methods of measurement of cholesterol metabolism are confounded by factors like diabetes mellitus, body weight and other pathologies including considerable hereditary hyperlipidemias biological variabilities that influence the efficiency of synthesis and intestinal absorption of cholesterol.

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Delineation of biochemical, molecular, and physiological changes accompanying bile acid pool size restoration in Cyp7a1−/− mice fed low levels of cholic acid

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00111.2012 ◽

2012 ◽

Vol 303 (2) ◽

pp. G263-G274 ◽

Cited By ~ 11

Author(s):

Ryan D. Jones ◽

Joyce J. Repa ◽

David W. Russell ◽

John M. Dietschy ◽

Stephen D. Turley

Keyword(s):

Cholic Acid ◽

Cholesterol Synthesis ◽

Target Genes ◽

Cholesterol Metabolism ◽

Cholesterol Absorption ◽

Pool Size ◽

Farnesoid X Receptor ◽

Cholesterol Concentration ◽

Intestinal Cholesterol Absorption ◽

Hepatic Expression

Cholesterol 7α-hydroxylase (CYP7A1) is the initiating and rate-limiting enzyme in the neutral pathway that coverts cholesterol to primary bile acids (BA). CYP7A1-deficient ( Cyp7a1−/−) mice have a depleted BA pool, diminished intestinal cholesterol absorption, accelerated fecal sterol loss, and increased intestinal cholesterol synthesis. To determine the molecular and physiological effects of restoring the BA pool in this model, adult female Cyp7a1−/− mice and matching Cyp7a1+/+ controls were fed diets containing cholic acid (CA) at modest levels [0.015, 0.030, and 0.060% (wt/wt)] for 15–18 days. A level of just 0.03% provided a CA intake of ∼12 μmol (4.8 mg) per day per 100 g body wt and was sufficient in the Cyp7a1−/− mice to normalize BA pool size, fecal BA excretion, fractional cholesterol absorption, and fecal sterol excretion but caused a significant rise in the cholesterol concentration in the small intestine and liver, as well as a marked inhibition of cholesterol synthesis in these organs. In parallel with these metabolic changes, there were marked shifts in intestinal and hepatic expression levels for many target genes of the BA sensor farnesoid X receptor, as well as genes involved in cholesterol transport, especially ATP-binding cassette (ABC) transporter A1 (ABCA1) and ABCG8. In Cyp7a1+/+ mice, this level of CA supplementation did not significantly disrupt BA or cholesterol metabolism, except for an increase in fecal BA excretion and marginal changes in mRNA expression for some BA synthetic enzymes. These findings underscore the importance of using moderate dietary BA levels in studies with animal models.

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Modifying Serum Plant Sterol Concentrations: Effects on Markers for Whole Body Cholesterol Metabolism in Children Receiving Parenteral Nutrition and Intravenous Lipids

Nutrients ◽

10.3390/nu11010120 ◽

2019 ◽

Vol 11 (1) ◽

pp. 120 ◽

Cited By ~ 4

Author(s):

Jogchum Plat ◽

Sabine Baumgartner ◽

Anita C.E. Vreugdenhil ◽

Maurice C. J. M. Konings ◽

Kara L. Calkins ◽

...

Keyword(s):

Parenteral Nutrition ◽

Plant Sterol ◽

Cholesterol Synthesis ◽

Cholesterol Metabolism ◽

Cholesterol Absorption ◽

Whole Body ◽

Serum Samples ◽

Intestinal Cholesterol Absorption ◽

Fold Reduction ◽

Endogenous Cholesterol

Background: Non-cholesterol sterols are validated markers for fractional intestinal cholesterol absorption (cholestanol) and endogenous cholesterol synthesis (lathosterol). This study’s objective was to evaluate markers for cholesterol synthesis and absorption in children exposed to two different intravenous lipid emulsions that rapidly change serum plant sterol concentrations as part of their parenteral nutrition (PN). Methods: Serum samples from two different studies were used: (1) nine PN-dependent children with intestinal failure associated liver disease (IFALD) whose soy-based, plant sterol-rich lipid (SO) was replaced with a fish-based, plant sterol-poor (FO) lipid; and (2) five neonates prescribed SO after birth. In the first study, samples were collected at baseline (prior to FO initiation) and after 3 and 6 months of FO. In study 2, samples were collected at 1 and 3 weeks of age. Results: In study 1, a 7-fold reduction in campesterol, a 12-fold reduction in sitosterol, and a 15-fold reduction in stigmasterol was observed 6 months after switching to FO. Serum cholesterol concentrations did not change, but cholesterol-standardized lathosterol increased (3-fold) and cholesterol-standardized cholestanol decreased (2-fold). In study 2, after 3 weeks of SO, sitosterol and campesterol concentrations increased 4-5 fold. At the same time, cholesterol-standardized lathosterol increased 69% and cholesterol-standardized cholestanol decreased by 29%. Conclusion: Based on these finding we conclude that changes in serum plant sterol concentrations might have direct effects on endogenous cholesterol synthesis, although this needs to be confirmed in future studies. Moreover, we speculate that this changed synthesis subsequently affects intestinal cholesterol absorption.

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Comment on: Non-Cholesterol Sterol Concentrations as Biomarkers for Cholesterol Absorption and Synthesis in Different Metabolic Disorders: A Systematic Review

Nutrients ◽

10.3390/nu11040780 ◽

2019 ◽

Vol 11 (4) ◽

pp. 780

Author(s):

Rime Jebai ◽

Semiu Gbadamosi ◽

Liliana Nassar Gorra ◽

Purnima Madhivanan

Keyword(s):

Systematic Review ◽

Metabolic Disorders ◽

Cholesterol Metabolism ◽

Cholesterol Absorption ◽

Health Related

The use of non-cholesterol sterols as biomarkers for cholesterol metabolism is well established in health-related topics [...]

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Associations between SNPs in Intestinal Cholesterol Absorption and Endogenous Cholesterol Synthesis Genes with Cholesterol Metabolism

Biomedicines ◽

10.3390/biomedicines9101475 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1475

Author(s):

Maite M. Schroor ◽

Fatma B. A. Mokhtar ◽

Jogchum Plat ◽

Ronald P. Mensink

Keyword(s):

Cholesterol Synthesis ◽

Cholesterol Metabolism ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Individual Variability ◽

Nucleotide Polymorphisms ◽

Intestinal Cholesterol Absorption ◽

Cross Sectional ◽

Tag Snp ◽

Endogenous Cholesterol

Single nucleotide polymorphisms (SNPs) have been associated with cholesterol metabolism and may partly explain large inter-individual variability in intestinal cholesterol absorption and endogenous cholesterol synthesis rates. This cross-sectional study therefore examined whether SNPs in genes encoding for proteins involved in intestinal cholesterol absorption (ABCG5, ABCG8, and NPC1L1) and endogenous cholesterol synthesis (CYP51A1, DHCR7, DHCR24, HMGCR, HSD17B7, LBR, and MSMO1) were associated with intestinal cholesterol absorption markers (total cholesterol (TC) standardized campesterol and sitosterol levels), an endogenous cholesterol synthesis marker (TC-standardized lathosterol levels), and serum low-density lipoprotein cholesterol (LDL-C) concentrations in a European cohort. ABCG5 (rs4245786) and the tag SNP ABCG8 (rs4245791) were significantly associated with serum campesterol and/or sitosterol levels. In contrast, NPC1L1 (rs217429 and rs217416) were significantly associated with serum lathosterol levels. The tag SNP in HMGCR (rs12916) and a SNP in LBR (rs12141732) were significantly associated with serum LDL-C concentrations. SNPs in the cholesterol absorption genes were not associated with serum LDL-C concentrations. SNPs in CYP51A1, DHCR24, HSD17B7, and MSMO1 were not associated with the serum non-cholesterol sterols and LDL-C concentrations. Given the variable efficiency of cholesterol-lowering interventions, the identification of SNPs associated with cholesterol metabolism could be a step forward towards personalized approaches.

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Flaxseed-Derived Peptide, IPPF, Inhibits Intestinal Cholesterol Absorption and Hepatic Cholesterol Synthesis in Caco-2 and HepG2 Cells

10.21203/rs.3.rs-680107/v1 ◽

2021 ◽

Author(s):

Xiaolan Bao ◽

yuan xingyu ◽

Xuexin Li ◽

Xiaojing Liu

Keyword(s):

Amino Acid ◽

Hepg2 Cells ◽

Cholesterol Synthesis ◽

Cholesterol Absorption ◽

Amino Acid Sequences ◽

Hepatic Cholesterol ◽

Intestinal Cholesterol Absorption ◽

Cholesterol Lowering ◽

Hepatic Cholesterol Synthesis ◽

Caco2 Cells

Abstract Background：Flaxseed peptide (FPs) showed serum cholesterol-lowering activity in SD rats fed a high-cholesterol diet, but the cholesterol-lowering amino acid sequences and mechanism of FPs were still unclear. Methods: FPs were separated via ultrafiltration, and the amino acid sequences of the selected fractions were determined via high-performance liquid chromatography- Electrospray Ionisation - Orbitrap- Mass spectrometry (HPLC-ESI-Orbitrap MS). These peptides then were synthesized by solid-phase synthesis (SPPS). IPPF with the highest CMSR was determined to exist in flaxseed protein by specific antibodies. The effects of IPPF on intestinal cholesterol absorption and hepatic cholesterol metabolism were investigated in Caco-2 cells and HepG2 cells.Results：1 kDa FP5 fraction had the highest cholesterol micelle solubility inhibition rate (CMSR) 72.39% compared with the other ultrafiltration fractions. Then Eleven peptides were identified from FP5. Ile-Pro-Pro-Phe (IPPF), with the highest CMSR 93.47%, was selected to research the cholesterol-lowering mechanism in Caco-2 and HepG2 cells. IPPF significantly reduces the amount of cholesterol transported in Caco2 cells and the amount of total cholesterol in HepG2 cells. IPPF significantly modulated the protein levels of NCP1L1 and ABCG5/8 in Caco2 cells and significantly reduced the mRNA levels of Srebp-2 and Hmgcr in HepG2 cells. Conclusion: IPPF inhibits cholesterol intestinal absorption through modulating the expression of cholesterol transporters in Caco-2 cells and reduces hepatic cholesterol synthesis through inhibiting the SREBP2-regulated mevalonate (HMGCR) pathway in HepG2 cells. IPPF is a new food-derived inhibitor of intestinal cholesterol absorption and hepatic cholesterol synthesis without side effects and provides a nutritional therapy component for hypercholesterolemia.

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Serum cholesterol precursor and plant sterol levels indicate increased de novo cholesterol synthesis and decreased intestinal cholesterol absorption in German gallstone patients

Zeitschrift für Gastroenterologie ◽

10.1055/s-0029-1241405 ◽

2009 ◽

Vol 47 (09) ◽

Author(s):

M Krawczyk ◽

JF Miquel ◽

D Lütjohann ◽

R Schirin-Shokan ◽

F Lammert

Keyword(s):

Serum Cholesterol ◽

Plant Sterol ◽

Cholesterol Synthesis ◽

De Novo ◽

Cholesterol Absorption ◽

Intestinal Cholesterol Absorption ◽

Cholesterol Precursor

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Absorption and metabolism of cholesterol in familial hypercholesterolemia

Clinical Science ◽

10.1042/cs0760297 ◽

1989 ◽

Vol 76 (3) ◽

pp. 297-301 ◽

Cited By ~ 8

Author(s):

Helena Gylling ◽

Tatu A. Miettinen

Keyword(s):

Cholesterol Synthesis ◽

Familial Hypercholesterolaemia ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Dietary Cholesterol ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Cholesterol Intake

1. The present study investigated the role of intestinal cholesterol absorption in the regulation of cholesterol metabolism and serum lipoprotein levels in 22 patients with heterozygous familial hypercholesterolaemia on low to normal cholesterol intake. 2. The results showed that the higher the dietary cholesterol absorption, the lower was the overall synthesis of cholesterol. Efficient cholesterol absorption actually reduced the elimination of cholesterol as faecal neutral sterols but not consistently as bile acids. 3. In multifactorial analysis, body mass index and dietary plant sterols were negatively associated with cholesterol absorption, but were unrelated to cholesterol synthesis. 4. Fractional cholesterol absorption was related only to the serum very-low-density triacylglycerol level. It was not associated with the total or low-density lipoprotein cholesterol levels. On the other hand, cholesterol synthesis was significantly associated with the serum concentrations of very-low-density lipoprotein and intermediate-density lipoprotein cholesterol and triacylglycerols, and with those of low-density lipoprotein triacylglycerols. 5. In conclusion, dietary cholesterol absorption is an essential regulator of cholesterol homoeostasis in familial hypercholesterolaemia, even in patients on low cholesterol intake.

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Exploring the effect of vitamin D3 supplementation on surrogate biomarkers of cholesterol absorption and endogenous synthesis in patients with type 2 diabetes—randomized controlled trial

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqaa149 ◽

2020 ◽

Vol 112 (3) ◽

pp. 538-547

Author(s):

Huicui Meng ◽

Nirupa R Matthan ◽

Edith Angellotti ◽

Anastassios G Pittas ◽

Alice H Lichtenstein

Keyword(s):

Type 2 Diabetes ◽

Serum Cholesterol ◽

Vitamin D3 ◽

Cholesterol Synthesis ◽

Cholesterol Absorption ◽

Cholesterol Lowering ◽

Ancillary Study ◽

Vitamin D3 Supplementation ◽

Endogenous Synthesis

ABSTRACT Background Inverse associations have been reported between serum 25-hydroxyvitamin D [25(OH)D] and circulating cholesterol concentrations in observational studies. Postulated mechanisms include reduced bioavailability of intestinal cholesterol and alterations in endogenous cholesterol synthesis. Objective To explore the effect of daily supplementation with 4000 IU/d vitamin D3 for 24 wk on surrogate biomarkers of cholesterol absorption (campesterol and β-sitosterol) and endogenous synthesis (lathosterol and desmosterol). Methods Ancillary study of The Vitamin D for Established Type 2 Diabetes (DDM2) trial. Patients with established type 2 diabetes (N = 127, 25–75 y, BMI 23–42 kg/m2) were randomly assigned to receive either 4000 IU vitamin D3 or placebo daily for 24 wk. Of participants without changes in cholesterol-lowering medications (n = 114), plasma surrogate cholesterol absorption and endogenous synthesis biomarker concentrations were measured and merged with available measures of serum LDL cholesterol and HDL cholesterol concentrations. Results At week 24, vitamin D3 supplementation significantly increased 25(OH)D concentrations (+21.5 ± 13.4 ng/mL) but not insulin secretion rates (primary outcome of the parent study) as reported previously. In this ancillary study there was no significant effect of vitamin D3 supplementation on serum cholesterol profile or surrogate biomarkers of cholesterol absorption and endogenous synthesis. Compared with participants not treated with cholesterol-lowering medications, those who were treated exhibited a greater reduction in plasma campesterol concentrations in the vitamin D3 but not placebo group (P-interaction = 0.011). Analyzing the data on the basis of cholesterol absorption status (hypo- versus hyperabsorbers) or cholesterol synthesis status (hypo- versus hypersynthesizers) did not alter these results. Conclusions Vitamin D3 supplementation for 24 wk had no significant effect on surrogate biomarkers of cholesterol absorption or endogenous synthesis, consistent with the lack of effect on serum cholesterol profile. Vitamin D3 supplementation resulted in greater reduction in campesterol concentrations in participants not using compared with those using cholesterol-lowering medications. Further studies are required. This trial was registered at clinicaltrials.gov as NCT01736865.

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