Association between non-responsiveness to plant sterol intervention and polymorphisms in cholesterol metabolism genes: a case-control study

Plant sterol (PS) consumption decreases low-density lipoprotein cholesterol (LDL-C) levels; however, high variability of responsiveness of lipid levels to PS intervention has been observed. We hypothesized that common single-nucleotide polymorphisms (SNPs) in the genes for the ATP binding cassette proteins G5 (ABCG5) and G8 (ABCG8), Niemann-Pick C1-like 1 (NPC1L1), or other proteins of the cholesterol pathway, would underline inter-individual variations in response to PS. Twenty-six hyperlipidemic subjects completed a randomized trial of 3 PS phases and a control phase. Three non-responders were identified who failed on 3 consecutive occasions to decrease either total cholesterol or LDL-C level vs. control. It was observed that after 3 PS phases compared with a control phase, cholesterol absorption changed to a lesser degree (–7.7% ± 10.8%) in the non-responders than in the top 3 responders (–22.1% ± 8.8%); however, cholesterol synthesis rates did not differ between sub-groups. No common polymorphisms in ABCG8, ABCG5, or NPC1L1 were demonstrated between the 3 top responders and the non-responders. Yet, 1 non-responsive subject did demonstrate a rare SNP in NPC1L1. Results indicate PS intake did not decrease cholesterol absorption rates to the same degree in certain subjects, possibly clarifying the inter-individual variability in the cholesterol-lowering effect; hence, this work should be expanded.

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The Effects of Anthocyanin-Rich Bilberry Extract on Transintestinal Cholesterol Excretion

Foods ◽

10.3390/foods10112852 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2852

Author(s):

Jimin Hong ◽

Minji Kim ◽

Bohkyung Kim

Keyword(s):

De Novo ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Lipoprotein Receptors ◽

Expression Of Genes ◽

Cholesterol Excretion ◽

Niemann Pick ◽

Bilberry Extract

Hypercholesterolemia is one of the modifiable and primary risk factors for cardiovascular diseases (CVD). Emerging evidence suggests the stimulation of transintestinal cholesterol excretion (TICE), the nonbiliary cholesterol excretion, using natural products can be an effective way to reduce CVD. Bilberry (Vaccinium myrtillus L.) has been reported to have cardioprotective effects by ameliorating oxidative stress, inflammation, and dyslipidemia. However, the role of bilberry in intestinal cholesterol metabolism is not well understood. To examine the effects of bilberry in intestinal cholesterol metabolism, we measured the genes for cholesterol flux and de novo synthesis in anthocyanin-rich bilberry extract (BE)-treated Caco-2 cells. BE significantly decreased the genes for cholesterol absorption, i.e., Niemann-Pick C1 Like 1 and ATP-binding cassette transporter A1 (ABCA1). In contrast, BE significantly upregulated ABCG8, the apical transporter for cholesterol. There was a significant induction of low-density lipoprotein receptors, with a concomitant increase in cellular uptake of cholesterol in BE-treated cells. The expression of genes for lipogenesis and sirtuins was altered by BE treatment. In the present study, BE altered the genes for cholesterol flux from basolateral to the apical membrane of enterocytes, potentially stimulating TICE. These results support the potential of BE in the prevention of hypercholesterolemia.

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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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The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism

Molecules ◽

10.3390/molecules27020523 ◽

2022 ◽

Vol 27 (2) ◽

pp. 523

Author(s):

Xiang Li ◽

Yan Xin ◽

Yuqian Mo ◽

Pavel Marozik ◽

Taiping He ◽

...

Keyword(s):

Cholesterol Metabolism ◽

Biological Activities ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

The Body ◽

Research Progress ◽

Intestinal Lumen ◽

Dose Response Relationship ◽

Liver X Receptor Α

Phytosterols are natural sterols widely found in plants that have a variety of physiological functions, and their role in reducing cholesterol absorption has garnered much attention. Although the bioavailability of phytosterols is only 0.5–2%, they can still promote cholesterol balance in the body. A mechanism of phytosterols for lowering cholesterol has now been proposed. They not only reduce the uptake of cholesterol in the intestinal lumen and affect its transport, but also regulate the metabolism of cholesterol in the liver. In addition, phytosterols can significantly reduce the plasma concentration of total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), with a dose-response relationship. Ingestion of 3 g of phytosterols per day can reach the platform period, and this dose can reduce LDL-C by about 10.7%. On the other hand, phytosterols can also activate the liver X receptor α-CPY7A1 mediated bile acids excretion pathway and accelerate the transformation and metabolism of cholesterol. This article reviews the research progress of phytosterols as a molecular regulator of cholesterol and the mechanism of action for this pharmacological effect.

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The Chylomicron: Relationship to Atherosclerosis

International Journal of Vascular Medicine ◽

10.1155/2012/784536 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Gerald H. Tomkin ◽

Daphne Owens

Keyword(s):

Cholesterol Synthesis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Structural Protein ◽

Chylomicron Particle ◽

Niemann Pick ◽

Chylomicron Formation ◽

The Relationship ◽

Ldl Composition

The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis.

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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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Alcohol Induces More Severe Fatty Liver Disease by Influencing Cholesterol Metabolism

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/7095684 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Bo Li ◽

Shan-Shan Lei ◽

Jie Su ◽

Xia-Miao Cai ◽

Hao Xu ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Liver Damage ◽

Fatty Liver Disease ◽

Cholesterol Metabolism ◽

Synergistic Effects ◽

Low Density Lipoprotein ◽

Dietary Cholesterol ◽

Density Lipoprotein ◽

Cholesterol Absorption

Objectives. Fatty liver disease (FLD) is a major cause of morbidity and mortality worldwide. Dietary cholesterol and alcohol consumption are important risk factors for the progression of FLD, but whether and how alcohol induces more severe FLD with cholesterol ingestion remain unclear. Herein, we mainly used the Lieber-DeCarli diet to establish the FLD mouse model to investigate the synergistic effects of alcohol and cholesterol metabolism on liver damage. The indices of aspartate transaminase (AST), alanine transaminase (ALT), low-density lipoprotein cholesterol (LDL-c), and total cholesterol (TC) levels, inflammation foci, and pathogenesis by hematoxylin and eosin (H&E) and Oil Red O staining revealed that alcohol induces more severe liver damage by influencing cholesterol metabolism, which might be primarily related to the influence of cholesterol absorption, synthesis, and excretion on the liver or small intestine. Moreover, inhibition of absorption of intestinal cholesterol, but not of fat, sucrose, and alcohol, absorption into the body’s metabolism by Ezetimibe, significantly improved FLD in rats fed with the high fat-cholesterol-sucrose and alcohol diet. These results showed that alcohol plays an important role in cholesterol metabolism in FLD.

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NPC1L1 Facilitates Sphingomyelin Absorption and Regulates Diet-Induced Production of VLDL/LDL-associated S1P

Nutrients ◽

10.3390/nu12092641 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2641

Author(s):

Yoshihide Yamanashi ◽

Tappei Takada ◽

Hideaki Yamamoto ◽

Hiroshi Suzuki

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

In Vivo Studies ◽

Lipid Mediator ◽

Low Density ◽

Dependent Manner ◽

Niemann Pick

Niemann-Pick C1-Like 1 (NPC1L1) is a cholesterol importer and target of ezetimibe, a cholesterol absorption inhibitor used clinically for dyslipidemia. Recent studies demonstrated that NPC1L1 regulates the intestinal absorption of several fat-soluble nutrients, in addition to cholesterol. The study was conducted to reveal new physiological roles of NPC1L1 by identifying novel dietary substrate(s). Very low-density lipoprotein and low-density lipoprotein (VLDL/LDL) are increased in Western diet (WD)-fed mice in an NPC1L1-dependent manner, so we comprehensively analyzed the NPC1L1-dependent VLDL/LDL components. Apolipoprotein M (apoM), a binding protein of sphingosine-1-phosphate (S1P: a lipid mediator), and S1P were NPC1L1-dependently increased in VLDL/LDL by WD feeding. S1P is metabolized from sphingomyelin (SM) and SM is abundant in WD, so we focused on intestinal SM absorption. In vivo studies with Npc1l1 knockout mice and in vitro studies with NPC1L1-overexpressing cells revealed that SM is a physiological substrate of NPC1L1. These results suggest a scenario in which dietary SM is absorbed by NPC1L1 in the intestine, followed by SM conversion to S1P and, after several steps, S1P is exported into the blood as the apoM-bound form in VLDL/LDL. Our findings provide insight into the functions of NPC1L1 for a better understanding of sphingolipids and S1P homeostasis.

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Cis- and Trans-Palmitoleic Acid Isomers Regulate Cholesterol Metabolism in Different Ways

Frontiers in Pharmacology ◽

10.3389/fphar.2020.602115 ◽

2020 ◽

Vol 11 ◽

Author(s):

Wen-wen Huang ◽

Bi-hong Hong ◽

Kai-kai Bai ◽

Ran Tan ◽

Ting Yang ◽

...

Keyword(s):

Bile Acids ◽

Palmitoleic Acid ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Cholesterol Homeostasis ◽

High Dose ◽

Intestinal Cholesterol Absorption ◽

Preventable Risk Factor

Hypercholesterolemia is a preventable risk factor for atherosclerosis and cardiovascular disease. However, the mechanisms whereby cis-palmitoleic acid (cPOA) and trans-palmitoleic acid (tPOA) promote cholesterol homeostasis and ameliorate hypercholesterolemia remain elusive. To investigate the effects of cPOA and tPOA on cholesterol metabolism and its mechanisms, we induced hypercholesterolemia in mice using a high-fat diet and then intragastrically administered cPOA or tPOA once daily for 4 weeks. tPOA administration reduced serum cholesterol, low-density lipoprotein, high-density lipoprotein, and hepatic free cholesterol and total bile acids (TBAs). Conversely, cPOA had no effect on these parameters except for TBAs. Histological examination of the liver, however, revealed that cPOA ameliorated hepatic steatosis more effectively than tPOA. tPOA significantly reduced the expression of 3-hydroxy-3-methyl glutaryl coenzyme reductase (HMGCR), LXRα, and intestinal Niemann-Pick C1-Like 1 (NPC1L1) and increased cholesterol 7-alpha hydroxylase (CYP7A1) in the liver, whereas cPOA reduced the expression of HMGCR and CYP7A1 in the liver and had no effect on intestinal NPC1L1. In summary, our results suggest that cPOA and tPOA reduce cholesterol synthesis by decreasing HMGCR levels. Furthermore, tPOA, but not cPOA, inhibited intestinal cholesterol absorption by downregulating NPC1L1. Both high-dose tPOA and cPOA may promote the conversion of cholesterol into bile acids by upregulating CYP7A1. tPOA and cPOA prevent hypercholesterolemia via distinct mechanisms.

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Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption

Science Advances ◽

10.1126/sciadv.abh3997 ◽

2021 ◽

Vol 7 (34) ◽

pp. eabh3997

Author(s):

Tao Long ◽

Yang Liu ◽

Yu Qin ◽

Russell A. DeBose-Boyd ◽

Xiaochun Li

Keyword(s):

Low Density Lipoprotein ◽

Transmembrane Helix ◽

Dietary Cholesterol ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Oligomeric State ◽

Cryo Electron Microscopy ◽

Niemann Pick ◽

Circulating Levels ◽

Insight Into

Polytopic Niemann-Pick C1-like 1 (NPC1L1) plays a major role in intestinal absorption of biliary cholesterol, vitamin E (VE), and vitamin K (VK). The drug ezetimibe inhibits NPC1L1-mediated absorption of cholesterol, lowering of circulating levels of low-density lipoprotein cholesterol. Here, we report cryo–electron microscopy structures of human NPC1L1 (hNPC1L1) bound to either cholesterol or a lipid resembling VE. These findings, together with functional assays, reveal that the same intramolecular channel in hNPC1L1 mediates transport of VE and cholesterol. hNPC1L1 exists primarily as a homodimer; dimerization is mediated by aromatic residues within a region of transmembrane helix 2 that exhibits a horizonal orientation in the membrane. Mutation of tryptophan-347 lies in this region disrupts dimerization and the resultant monomeric NPC1L1 exhibits reduced efficiency of cholesterol uptake. These findings identify the oligomeric state of hNPC1L1 as a target for therapies that inhibit uptake of dietary cholesterol and reduce the incidence of cardiovascular disease.

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SAT-456 Reduced Cholesterol Absorption and Synthesis Markers in Patients with Hyperthyroidism Due to Graves’ Disease

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.888 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Tomoko Nagamine ◽

Kyoko Inagaki ◽

Shunsuke Kobayashi ◽

Yuki Shuto ◽

Mototsugu Nagao ◽

...

Keyword(s):

Cholesterol Synthesis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Surface Expression ◽

Cell Surface Expression ◽

Graves Disease ◽

Euthyroid State ◽

Niemann Pick ◽

Coa Reductase

Abstract Background:Thyroid hormones have been reported to promote cell-surface expression of low-density lipoprotein receptor (LDL-R), and also increase mRNA expression of HMG-CoA reductase at the same time. Since LDL cholesterol (LDL-C) uptake via LDL-R is relatively superior to cholesterol synthesis in hyperthyroidism, plasma LDL-C levels can be lower as compared to euthyroid state. Conversely, hypothyroidism can increase plasma LDL-C levels because cholesterol absorption via Niemann-Pick C1-like 1 has been suggested to increase in hypothyroidism. However, there have been no reports about changes of cholesterol absorption and synthesis markers by the treatment of hyperthyroidism in patients with Graves’ disease. Patients and method: We collected plasma samples from patients with hyperthyroidism, who were diagnosed as Graves’ disease (n=17, M/F: 4/13, age: 24-70 years old). Thyroid hormones, general lipid profiles (Total cholesterol: TC, LDL-C, high-density lipoprotein cholesterol: HDL-C and triglyceride: TG), apolipoproteins, markers of cholesterol synthesis (lathosterol) and absorption (campesterol, sitosterol, cholestanol), lipoprotein lipase (LPL), and proprotein convertase subtilisin/kexin type 9 (PCSK9) were analyzed before treatment, and at euthyroid state (eu), 3 and 6 months after attaining euthyroid state (eu-3M and eu-6M). Result: It took 159.2±108.6 days to attain euthyroid state by the thiamazole treatment. TC, LDL-C and HDL-C levels were increased at eu (TC, 144.5±26.7 to 225.0±61.6; LDL-C, 77.8±20.9 to 138.9±43.9; HDL-C, 49.7±12.6 to 67.9±20.0 mg/dL: P<0.0001 vs before treatment, respectively). Such changes remained at eu-3M and eu-6M. TG was not changed at eu, but significantly increased at eu-6M (85.0±49.1 to 113.7±60.8 mg/dL, P=0.02). Cholesterol absorption markers were increased at eu, eu-3M and eu-6M (e.g. campesterol, 2.6±1.2 to 4.9±2.3; sitosterol, 1.5±0.6 to 2.9±1.4; cholestanol, 1.9±0.6 to 3.2±1.1 μg/mL: P<0.0001, eu vs before treatment, respectively). Cholesterol synthesis marker was increased at eu, eu-3M and eu-6M (e.g. lathosterol, 1.8±0.7 to 2.3±0.9 μg/mL: P=0.005, eu vs before treatment). Both LPL and PCSK9 were also increased at eu, eu-3M and eu-6M. Conclusion: These data suggest that both cholesterol absorption and synthesis are downregulated in patients with hyperthyroidism due to Graves’ disease and can be restored by attaining euthyroid state. In turn, LDL-C and TG levels should be carefully monitored during the treatment of Graves’ disease because hyperlipidemia could emerge in euthyroid state.

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