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

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

Current Medicinal Chemistry ◽

10.2174/0929867326666190822154701 ◽

2019 ◽

Vol 26 (37) ◽

pp. 6704-6723 ◽

Cited By ~ 7

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.

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Ezetimibe and Improving Cardiovascular Outcomes: Current Evidence and Perspectives

Cardiology Research and Practice ◽

10.1155/2020/9815016 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Akshyaya Pradhan ◽

Monika Bhandari ◽

Rishi Sethi

Keyword(s):

Statin Therapy ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Cardiovascular Outcomes ◽

Current Evidence ◽

High Dose ◽

Residual Cardiovascular Risk ◽

Intestinal Cholesterol Absorption ◽

Cholesterol Absorption Inhibitor

Low-density lipoprotein lowering with statins has convincingly and consistently proven to reduce cardiovascular events in both primary and secondary prevention. However, despite high-dose statin therapy, residual cardiovascular risk remains and many patients also do not tolerate statins. Ezetimibe was initially projected as a frontline alternative to statin. It is an intestinal cholesterol absorption inhibitor with modest LDL lowering effects. But, major studies failed to demonstrate any beneficial effect of CV outcomes, and the drug was relegated to oblivion. IMPROVE-IT, a contemporary, large, and well-designed trial, unequivocally demonstrated reduction in CV outcomes with ezetimibe when added to statin therapy. The benefits are seen in both sexes, elderly, CKD, diabetes mellitus, and in patients with prior CABG. It also reduces biomarkers and induces plaque regression like statins. The drug has now established itself as an add-on therapy to statin when monotherapy fails to achieve LDL goals and when it is not tolerated. The combination therapy has excellent safety and efficacy record. It has now been endorsed by major guidelines too in management of dyslipidemia. Yes, ezetimibe can indeed improve cardiovascular outcomes!

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Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR-/- mice by altering intestinal cholesterol fluxes

Thrombosis and Haemostasis ◽

10.1160/th16-01-0043 ◽

2016 ◽

Vol 116 (09) ◽

pp. 565-577 ◽

Cited By ~ 6

Author(s):

Gemma Brufau ◽

Marion J. J. Gijbels ◽

Ine M. J. Wolfs ◽

Saskia van der Velden ◽

Chantal C. H. Pöttgens ◽

...

Keyword(s):

Inflammatory Responses ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Homeostasis ◽

Liver Cholesterol ◽

Specific Cell ◽

Low Density ◽

Atherosclerosis Development ◽

Deficient Mice

SummaryInflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower myeloid cell accumulation and more apoptosis in the lesions. Additionally, a profound reduction in plasma and liver cholesterol was observed upon myeloid IL-10R1 deficiency, which was reflected in plaque lipid content. This decreased hypercholesterolaemia was associated with lowered very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, likely as a response to decreased intestinal cholesterol absorption. In addition, IL-10R1 deficient mice demonstrated substantially higher faecal sterol loss caused by increased non-biliary cholesterol efflux. The induction of this process was linked to impaired ACAT2-mediated esterification of liver and plasma cholesterol. Overall, myeloid cells do not contribute to IL-10-mediated atheroprotection. In addition, this study demonstrates a novel connection between IL-10-mediated inflammation and cholesterol homeostasis in atherosclerosis. These findings make us reconsider IL-10 as a beneficial influence on atherosclerosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

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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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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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Pinto Beans (Phaseolus vulgaris L.) Lower Non-HDL Cholesterol in Hamsters Fed a Diet Rich in Saturated Fat and Act on Genes Involved in Cholesterol Homeostasis

Journal of Nutrition ◽

10.1093/jn/nxz044 ◽

2019 ◽

Vol 149 (6) ◽

pp. 996-1003 ◽

Cited By ~ 2

Author(s):

An Tien Nguyen ◽

Sami Althwab ◽

Haowen Qiu ◽

Richard Zbasnik ◽

Carlos Urrea ◽

...

Keyword(s):

Fatty Acids ◽

Molecular Mechanisms ◽

Cholesterol Metabolism ◽

Saturated Fatty Acids ◽

Saturated Fat ◽

Density Lipoprotein ◽

Cholesterol Homeostasis ◽

Liver Cholesterol ◽

Intestinal Cholesterol Absorption ◽

Pinto Beans

ABSTRACT Background Pinto beans contain multiple active agents such as polyphenols, flavonoids, and saponins, and have been shown to lower cholesterol, but the mechanisms involved in this effect have not been explored. Objective This study was to investigate the changes in cholesterol metabolism in response to whole pinto beans (wPB) and their hulls (hPB) supplemented into a diet rich in saturated fat and the molecular mechanisms potentially responsible for these effects in hamsters. Methods Forty-four 9-wk-old male Golden Syrian hamsters were randomly assigned to 4 diet groups (n = 11), including a 5% (wt:wt) fat diet [normal-fat diet (NF)], a 15% (wt:wt) fat diet [diet rich in saturated fat (HSF), saturated fatty acids accounted for 70% of total fatty acids], or HSF supplemented with 5% (wt:wt) wPB or 0.5% (wt:wt) hPB for 4 wk. Plasma, liver, intestinal, and fecal samples were collected to evaluate multiple cholesterol markers and gene targets. Results The plasma non-high-density lipoprotein (non-HDL) concentration was significantly reduced in the wPB- and hPB-supplemented groups by 31.9 ± 3.5% and 53.6 ± 3.2%, respectively, compared with the HSF group (P < 0.01), to concentrations comparable with the NF group. The wPB-supplemented hamsters had significantly lower liver cholesterol (45.1%, P < 0.001) and higher fecal cholesterol concentrations (94.8%, P = 0.001) than those fed the HSF. The expressions of hepatic 3-hydroxy-3-methylglutaryl CoA reductase (Hmgcr) and small intestinal acyl-coenzyme A: cholesterol acyltransferase 2 (Acat2) were significantly decreased in animals administered wPB (by 89.1% and 63.8%, respectively) and hPB (by 72.9% and 47.7%, respectively) compared with their HSF-fed counterparts (P < 0.05). The wPB normalized the expression of Acat2 to the level of the NF group. Conclusion Pinto beans remediated high cholesterol induced by HSF in male hamsters by decreasing hepatic cholesterol synthesis and intestinal cholesterol absorption, effects which were partially exerted by the hulls.

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

Applied Physiology Nutrition and Metabolism ◽

10.1139/h08-041 ◽

2008 ◽

Vol 33 (4) ◽

pp. 728-734 ◽

Cited By ~ 23

Author(s):

Iwona Rudkowska ◽

Suhad S. AbuMweis ◽

Catherine Nicolle ◽

Peter J.H. Jones

Keyword(s):

Plant Sterol ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Individual Variability ◽

Nucleotide Polymorphisms ◽

Control Phase ◽

Individual Variations ◽

Niemann Pick

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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Polyphenols can Potentially Prevent Atherosclerosis and Cardiovascular Disease by Modulating Macrophage Cholesterol Metabolism

Current Molecular Pharmacology ◽

10.2174/1874467213666200320153410 ◽

2020 ◽

Vol 14 (2) ◽

pp. 175-190 ◽

Cited By ~ 3

Author(s):

Fumiaki Ito

Keyword(s):

Cholesterol Efflux ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Arterial Disease ◽

Epidemiological Studies ◽

Cholesterol Homeostasis ◽

Cholesterol Accumulation ◽

Cholesterol Uptake ◽

Patients At Risk

Background: Arterial atherosclerosis is the main pathological cause of coronary artery disease and peripheral arterial disease. Atherosclerosis is a chronic condition characterized by the presence of cholesterol-rich macrophages in the arterial intima. Accumulation of cholesterol in these macrophages is due to increased oxidation of low-density lipoprotein (LDL) and its uptake via scavenger receptors on the macrophages. Cholesterol efflux from the cholesterol-laden macrophages into high-density lipoprotein (HDL) is also a key process in maintaining cholesterol homeostasis and prevention of cholesterol accumulation. Four pathways for the efflux of cholesterol to HDL exist in macrophages, including passive and active pathways. Several HDL characteristics determine cholesterol efflux capacity, namely composition, oxidative status, and HDL size. Oxidation of LDL and HDL as well as any imbalance in cholesterol uptake and efflux could lead to accumulation of cholesterol in macrophages and initiation of atherosclerogenesis. Conclusion: Epidemiological studies have demonstrated that polyphenol-rich foods reduce cardiovascular events in the general population and in patients at risk of cardiovascular diseases. Many studies have reported that polyphenols in polyphenol-rich foods have anti-atherosclerotic properties by preventing cholesterol accumulation in macrophages through the suppression of lipoproteins oxidation and regulation of cholesterol uptake and efflux.

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