Nutrients

Editorial

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4 pages, 181 KiB

Open AccessEditorial

From Dietary Cholesterol to Blood Cholesterol

by Frans Stellaard

Nutrients 2023, 15(14), 3086; https://doi.org/10.3390/nu15143086 - 10 Jul 2023

Cited by 1 | Viewed by 1699

Abstract

The Nutrients’ Special Issue “From dietary cholesterol to blood cholesterol” aims to supply existing knowledge and novel new research data about human cholesterol (C) fluxes [...] Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

Research

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24 pages, 5035 KiB

Open AccessArticle

Activation of Liver X Receptors and Peroxisome Proliferator-Activated Receptors by Lipid Extracts of Brown Seaweeds: A Potential Application in Alzheimer’s Disease?

by Nikita Martens, Na Zhan, Gardi Voortman, Frank P. J. Leijten, Connor van Rheenen, Suzanne van Leerdam, Xicheng Geng, Michiel Huybrechts, Hongbing Liu, Johan W. Jonker, Folkert Kuipers, Dieter Lütjohann, Tim Vanmierlo and Monique T. Mulder

Nutrients 2023, 15(13), 3004; https://doi.org/10.3390/nu15133004 - 30 Jun 2023

Cited by 6 | Viewed by 2734

Abstract

The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) are involved in the regulation of multiple biological processes, including lipid metabolism and inflammation. The activation of these receptors has been found to have neuroprotective effects, making them interesting therapeutic targets for [...] Read more.

The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) are involved in the regulation of multiple biological processes, including lipid metabolism and inflammation. The activation of these receptors has been found to have neuroprotective effects, making them interesting therapeutic targets for neurodegenerative disorders such as Alzheimer’s Disease (AD). The Asian brown seaweed Sargassum fusiforme contains both LXR-activating (oxy)phytosterols and PPAR-activating fatty acids. We have previously shown that dietary supplementation with lipid extracts of Sargassum fusiforme prevents disease progression in a mouse model of AD, without inducing adverse effects associated with synthetic pan-LXR agonists. We now determined the LXRα/β- and PPARα/γ-activating capacity of lipid extracts of six European brown seaweed species (Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, Himanthalia elongata, Saccharina latissima, and Sargassum muticum) and the Asian seaweed Sargassum fusiforme using a dual luciferase reporter assay. We analyzed the sterol and fatty acid profiles of the extracts by GC-MS and UPLC MS/MS, respectively, and determined their effects on the expression of LXR and PPAR target genes in several cell lines using quantitative PCR. All extracts were found to activate LXRs, with the Himanthalia elongata extract showing the most pronounced efficacy, comparable to Sargassum fusiforme, for LXR activation and transcriptional regulation of LXR-target genes. Extracts of Alaria esculenta, Fucus vesiculosus, and Saccharina latissima showed the highest capacity to activate PPARα, while extracts of Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, and Sargassum muticum showed the highest capacity to activate PPARγ, comparable to Sargassum fusiforme extract. In CCF-STTG1 astrocytoma cells, all extracts induced expression of cholesterol efflux genes (ABCG1, ABCA1, and APOE) and suppressed expression of cholesterol and fatty acid synthesis genes (DHCR7, DHCR24, HMGCR and SREBF2, and SREBF1, ACACA, SCD1 and FASN, respectively). Our data show that lipophilic fractions of European brown seaweeds activate LXRs and PPARs and thereby modulate lipid metabolism. These results support the potential of brown seaweeds in the prevention and/or treatment of neurodegenerative diseases and possibly cardiometabolic and inflammatory diseases via concurrent activation of LXRs and PPARs. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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19 pages, 1143 KiB

Open AccessArticle

Phytosterols and Cardiovascular Risk Evaluated against the Background of Phytosterolemia Cases—A German Expert Panel Statement

by Eberhard Windler, Frank-Ulrich Beil, Heiner K. Berthold, Ioanna Gouni-Berthold, Ursula Kassner, Gerald Klose, Stefan Lorkowski, Winfried März, Klaus G. Parhofer, Jogchum Plat, Günter Silbernagel, Elisabeth Steinhagen-Thiessen, Oliver Weingärtner, Birgit-Christiane Zyriax and Dieter Lütjohann

Nutrients 2023, 15(4), 828; https://doi.org/10.3390/nu15040828 - 6 Feb 2023

Cited by 8 | Viewed by 3607

Abstract

Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This [...] Read more.

Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This expert statement examines the possibility of specific atherogenicity of PSs based on sterol metabolism, experimental, animal, and human data. Observational studies show no evidence that plasma PS concentrations would be associated with an increased risk of atherosclerosis or cardiovascular (CV) events. Since variants of the ABCG5/8 transporter affect the absorption of cholesterol and non-cholesterol sterols, Mendelian randomization studies examining the effects of ABCG5/8 polymorphisms cannot support or refute the potential atherogenic effects of PSs due to pleiotropy. In homozygous patients with phytosterolemia, total PS concentrations are ~4000% higher than under physiological conditions. The prevalence of atherosclerosis in these individuals is variable and may mainly relate to concomitant elevated LDL-C. Consuming PS-enriched foods increases PS concentrations by ~35%. Hence, PSs, on a molar basis, would need to have 20–40 times higher atherogenicity than cholesterol to offset their cholesterol reduction benefit. Based on their LDL-C lowering and absence of adverse safety signals, PSs offer a dietary approach to cholesterol management. However, their clinical benefits have not been established in long-term CV endpoint studies. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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16 pages, 1489 KiB

Open AccessArticle

Consuming High-Fat and Low-Fat Ground Beef Depresses High-Density and Low-Density Lipoprotein Cholesterol Concentrations, and Reduces Small, Dense Low-Density Lipoprotein Particle Abundance

by Jason R. Lytle, Tara Price, Stephen F. Crouse, Dana R. Smith, Rosemary L. Walzem and Stephen B. Smith

Nutrients 2023, 15(2), 337; https://doi.org/10.3390/nu15020337 - 10 Jan 2023

Cited by 4 | Viewed by 2983

Abstract

We hypothesized that consumption of high-fat (HF) ground beef (24% fat) would not affect plasma concentrations of high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein (LDL-C), whereas low-fat (LF) ground beef (5% fat) would decrease HDL-C and LDL-C concentrations. In a randomized 2-period crossover, [...] Read more.

We hypothesized that consumption of high-fat (HF) ground beef (24% fat) would not affect plasma concentrations of high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein (LDL-C), whereas low-fat (LF) ground beef (5% fat) would decrease HDL-C and LDL-C concentrations. In a randomized 2-period crossover, controlled feeding trial, 25 men (mean age and body mass index, 40 years and 31.2) consumed 115-g HF or LF patties, 5/week for 5 weeks with a 4-week washout. The HF treatment increased % energy from fat (p = 0.006) and saturated fat (p = 0.004) and tended (p = 0.060) to depress % energy from carbohydrates. The HF and LF treatments decreased the plasma concentrations of HDL-C (p = 0.001) and LDL-C (p = 0.011). Both ground beef treatments decreased the abundance of HDL_3a and increased the abundance of HDL₃ (p ≤ 0.003); the LF treatment also decreased the abundance of HDL_2b and HDL_2a (p ≤ 0.012). The HF and LF treatments decreased the abundance of LDL₃ and LDL₄ (p ≤ 0.024) and the HF treatment also decreased LDL₅ (p = 0.041). Contrary to our hypothesis, the HF treatment decreased plasma HDL-C and LDL-C concentrations despite increased saturated fat intake, and both treatments decreased the abundance of smaller, denser LDL subfractions. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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10 pages, 257 KiB

Open AccessArticle

Serum Low Density Lipoprotein Cholesterol Concentration Is Not Dependent on Cholesterol Synthesis and Absorption in Healthy Humans

by Frans Stellaard, Sabine Baumgartner, Ronald Mensink, Bjorn Winkens, Jogchum Plat and Dieter Lütjohann

Nutrients 2022, 14(24), 5370; https://doi.org/10.3390/nu14245370 - 17 Dec 2022

Cited by 3 | Viewed by 2147

Abstract

Introduction. Pharmacological reduction of cholesterol (C) synthesis and C absorption lowers serum low-density lipoprotein C (LDL-C) concentrations. We questioned whether high baseline C synthesis or C absorption translates into high serum LDL-C concentrations or if there was no connection. Therefore, we studied the [...] Read more.

Introduction. Pharmacological reduction of cholesterol (C) synthesis and C absorption lowers serum low-density lipoprotein C (LDL-C) concentrations. We questioned whether high baseline C synthesis or C absorption translates into high serum LDL-C concentrations or if there was no connection. Therefore, we studied the association between serum LDL-C and C synthesis or C absorption in healthy subjects. Methods. Three published data sets of young subjects on different diets (study 1), mildly hypercholesterolemic subjects without cardiovascular disease (study 2) and healthy controls of the Framingham study (study 3) were used. The three study populations varied in sex, age, and weight. C synthesis and C fractional absorption rate (FAR) were measured with fecal sterol balance and stable isotope techniques (studies 1 and 2). Additionally, serum lathosterol and campesterol concentrations corrected for the serum total C concentration (R_lathosterol and R_campesterol) were used as markers for hepatic C synthesis and C FAR, respectively (studies 1–3). Linear regression analysis was applied to evaluate associations between LDL-C, C synthesis, and C absorption. Results. Seventy-three, 37, and 175 subjects were included in studies 1, 2, and 3, respectively. No statistically significant associations were found between LDL-C and the measured C synthesis and C FAR, nor for R_lathosterol and R_campesterol in any of the study groups. This lack of associations was confirmed by comparing the male subjects of studies 1 and 2. Study 1 subjects had a 50% lower serum LDL-C than the study 2 subjects (p < 0.01), but not a lower C synthesis, C FAR, R-lathosterol, or R_campesterol. Conclusions. Under physiological conditions, C synthesis and C FAR are not major determinants of circulating serum LDL-C concentrations in healthy subjects. The results need to be confirmed in large-scale studies in healthy subjects and patients at risk for cardiovascular disease. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

15 pages, 3095 KiB

Open AccessArticle

A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding

by Yared Paalvast, Enchen Zhou, Yvonne J. W. Rozendaal, Yanan Wang, Albert Gerding, Theo H. van Dijk, Jan Freark de Boer, Patrick C. N. Rensen, Ko Willems van Dijk, Jan A. Kuivenhoven, Barbara M. Bakker, Natal A. W. van Riel and Albert K. Groen

Nutrients 2022, 14(22), 4936; https://doi.org/10.3390/nu14224936 - 21 Nov 2022

Cited by 2 | Viewed by 2007

Abstract

Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice [...] Read more.

Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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11 pages, 552 KiB

Open AccessArticle

Effects of Diet-Induced Weight Loss on Plasma Markers for Cholesterol Absorption and Synthesis: Secondary Analysis of a Randomized Trial in Abdominally Obese Men

by Sultan Mashnafi, Jogchum Plat, Ronald P. Mensink, Peter J. Joris, Yvo H. A. M. Kusters, Alfons J. H. M. Houben, Coen D. A. Stehouwer, Casper G. Schalkwijk and Sabine Baumgartner

Nutrients 2022, 14(8), 1546; https://doi.org/10.3390/nu14081546 - 8 Apr 2022

Cited by 3 | Viewed by 2311

Abstract

Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the [...] Read more.

Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the effect of weight loss on these metabolic characteristics is, however, limited, while the role of the different fat compartments has not been studied into detail. In a randomized trial, abdominally obese men (N = 54) followed a 6-week very low caloric (VLCD) diet, followed by a 2 week weight-maintenance period. Non-cholesterol sterols were measured at baseline and after 8 weeks, and compared to levels in lean participants (N = 25). After weight loss, total cholesterol (TC)-standardized cholestanol levels increased by 0.18 µmol/mmol (p < 0.001), while those of campesterol and lathosterol decreased by 0.25 µmol/mmol (p < 0.05) and 0.39 µmol/mmol (p < 0.001), respectively. Moreover, after weight loss, TC-standardized lathosterol and cholestanol levels were comparable to those of lean men. Increases in TC-standardized cholestanol after weight loss were significantly associated with changes in waist circumference (p < 0.01), weight (p < 0.001), BMI (p < 0.001) and visceral fat (p < 0.01), but not with subcutaneous and intrahepatic lipids. In addition, cross-sectional analysis showed that visceral fat fully mediated the association between BMI and TC-standardized cholestanol levels. Intrahepatic lipid content was a partial mediator for the association between BMI and TC-standardized lathosterol levels. In conclusion, diet-induced weight loss decreased cholesterol synthesis and increased cholesterol absorption. The increase in TC-standardized cholestanol levels was not only related to weight loss, but also to a decrease in visceral fat volume. Whether these metabolic changes ameliorate other metabolic risk factors needs further study. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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15 pages, 580 KiB

Open AccessArticle

Non-Cholesterol Sterols in Breast Milk and Risk of Allergic Outcomes in the First Two Years of Life

by Lieve van Brakel, Carel Thijs, Ronald P. Mensink, Dieter Lütjohann and Jogchum Plat

Nutrients 2022, 14(4), 766; https://doi.org/10.3390/nu14040766 - 11 Feb 2022

Cited by 4 | Viewed by 2792

Abstract

This study aimed to explore associations between non-cholesterol sterol concentrations in breast milk and allergic outcomes in children aged two. Data from the KOALA Birth Cohort Study, the Netherlands, were used. Non-cholesterol sterols were analyzed by gas–liquid chromatography–mass spectrometry in breast milk sampled [...] Read more.

This study aimed to explore associations between non-cholesterol sterol concentrations in breast milk and allergic outcomes in children aged two. Data from the KOALA Birth Cohort Study, the Netherlands, were used. Non-cholesterol sterols were analyzed by gas–liquid chromatography–mass spectrometry in breast milk sampled one-month postpartum (N = 311). Sterols were selected for each allergic outcome, i.e., eczema, wheeze, and allergic sensitization, prior to analyses. Associations between the selected sterols with allergic outcomes were analyzed using multiple logistic regression to calculate odds ratios (ORs). The odds of eczema in the first two years of life were lower with higher concentrations of cholestanol (OR (95%CI): 0.98 (0.95; 1.00), p = 0.04), lanosterol (0.97 (0.95; 1.00), p = 0.02), lathosterol (0.93 (0.87; 0.99), p = 0.02), and stigmasterol (0.51 (0.29; 0.91), p = 0.02) in breast milk sampled one-month postpartum. None of the sterols were associated with wheeze in the first two years of life. The odds of allergic sensitization at age two were lower with higher concentrations of campesterol in breast milk (OR (95%CI): 0.81 (0.70; 0.95), p = 0.01). In conclusion, our data suggest that exposure to higher non-cholesterol sterol concentrations in breast milk may indeed be associated with the prevention of allergic outcomes in the first two years of life. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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Review

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12 pages, 644 KiB

Open AccessEditor’s ChoiceReview

Measurement of Serum Low Density Lipoprotein Cholesterol and Triglyceride-Rich Remnant Cholesterol as Independent Predictors of Atherosclerotic Cardiovascular Disease: Possibilities and Limitations

by Dieter Lütjohann, Hans-Ulrich Klör and Frans Stellaard

Nutrients 2023, 15(9), 2202; https://doi.org/10.3390/nu15092202 - 5 May 2023

Cited by 8 | Viewed by 3305

Abstract

The serum low density lipoprotein cholesterol (LDL-C) concentration is the dominant clinical parameter to judge a patient’s risk of developing cardiovascular disease (CVD). Recent evidence supports the theory that cholesterol in serum triglyceride-rich lipoproteins (TRLs) contributes significantly to the atherogenic risk, independent of [...] Read more.

The serum low density lipoprotein cholesterol (LDL-C) concentration is the dominant clinical parameter to judge a patient’s risk of developing cardiovascular disease (CVD). Recent evidence supports the theory that cholesterol in serum triglyceride-rich lipoproteins (TRLs) contributes significantly to the atherogenic risk, independent of LDL-C. Therefore, combined analysis of both targets and adequate treatment may improve prevention of CVD. The validity of TRL-C calculation is solely dependent on the accuracy of the LDL-C measurement. Direct measurement of serum LDL- C is more accurate than established estimation procedures based upon Friedewald, Martin–Hopkins, or Sampson equations. TRL-C can be easily calculated as total C minus high density lipoprotein C (HDL-C) minus LDL-C. Enhanced serum LDL-C or TRL-C concentrations require different therapeutic approaches to lower the atherogenic lipoprotein C. This review describes the different atherogenic lipoproteins and their possible analytical properties and limitations. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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26 pages, 2625 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles of Gut Microbial Modulation of Bile Acid Composition in the Etiology of Cardiovascular Diseases

by Tess Yntema, Debby P. Y. Koonen and Folkert Kuipers

Nutrients 2023, 15(8), 1850; https://doi.org/10.3390/nu15081850 - 12 Apr 2023

Cited by 20 | Viewed by 5264

Abstract

Despite advances in preventive measures and treatment options, cardiovascular disease (CVD) remains the number one cause of death globally. Recent research has challenged the traditional risk factor profile and highlights the potential contribution of non-traditional factors in CVD, such as the gut microbiota [...] Read more.

Despite advances in preventive measures and treatment options, cardiovascular disease (CVD) remains the number one cause of death globally. Recent research has challenged the traditional risk factor profile and highlights the potential contribution of non-traditional factors in CVD, such as the gut microbiota and its metabolites. Disturbances in the gut microbiota have been repeatedly associated with CVD, including atherosclerosis and hypertension. Mechanistic studies support a causal role of microbiota-derived metabolites in disease development, such as short-chain fatty acids, trimethylamine-N-oxide, and bile acids, with the latter being elaborately discussed in this review. Bile acids represent a class of cholesterol derivatives that is essential for intestinal absorption of lipids and fat-soluble vitamins, plays an important role in cholesterol turnover and, as more recently discovered, acts as a group of signaling molecules that exerts hormonal functions throughout the body. Studies have shown mediating roles of bile acids in the control of lipid metabolism, immunity, and heart function. Consequently, a picture has emerged of bile acids acting as integrators and modulators of cardiometabolic pathways, highlighting their potential as therapeutic targets in CVD. In this review, we provide an overview of alterations in the gut microbiota and bile acid metabolism found in CVD patients, describe the molecular mechanisms through which bile acids may modulate CVD risk, and discuss potential bile-acid-based treatment strategies in relation to CVD. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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13 pages, 674 KiB

Open AccessReview

Severe Dyslipidemia Mimicking Familial Hypercholesterolemia Induced by High-Fat, Low-Carbohydrate Diets: A Critical Review

by Veera Houttu, Aldo Grefhorst, Danny M. Cohn, Johannes H. M. Levels, Jeanine Roeters van Lennep, Erik S. G. Stroes, Albert K. Groen and Tycho R. Tromp

Nutrients 2023, 15(4), 962; https://doi.org/10.3390/nu15040962 - 15 Feb 2023

Cited by 7 | Viewed by 6883

Abstract

Emerging studies in the literature describe an association between high-fat, low-carbohydrate diets and severe hypercholesterolemia consistent with the levels observed in patients with (homozygous) familial hypercholesterolemia (FH). High levels of low-density lipoprotein cholesterol (LDL-C) may result from the reduced clearance of LDL particles [...] Read more.

Emerging studies in the literature describe an association between high-fat, low-carbohydrate diets and severe hypercholesterolemia consistent with the levels observed in patients with (homozygous) familial hypercholesterolemia (FH). High levels of low-density lipoprotein cholesterol (LDL-C) may result from the reduced clearance of LDL particles from the circulation, the increased production of their precursor, or a combination of both. The increased intake of (saturated) fat and cholesterol, combined with limited to no intake of carbohydrates and fiber, are the main features of diets linked to hypercholesterolemia. However, several observations in previous studies, together with our observations from our lipid clinic, do not provide a definitive pathophysiological explanation for severe hypercholesterolemia. Therefore, we review these findings and possible pathophysiological explanations as well as opportunities for future research. Altogether, clinicians should rule out high-fat, low-carbohydrate diets as a possible cause for hypercholesterolemia in patients presenting with clinical FH in whom no mutation is found and discuss dietary modifications to durably reduce LDL-C levels and cardiovascular disease risk. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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10 pages, 1087 KiB

Open AccessReview

Is microRNA-33 an Appropriate Target in the Treatment of Atherosclerosis?

by Malgorzata Sidorkiewicz

Nutrients 2023, 15(4), 902; https://doi.org/10.3390/nu15040902 - 10 Feb 2023

Cited by 6 | Viewed by 2033

Abstract

The maintenance of cholesterol homeostasis is a complicated process involving regulation of cholesterol synthesis, dietary uptake and bile acid synthesis and excretion. Reverse cholesterol transport, described as the transfer of cholesterol from non-hepatic cells, including foam cells in atherosclerotic plaques, to the liver [...] Read more.

The maintenance of cholesterol homeostasis is a complicated process involving regulation of cholesterol synthesis, dietary uptake and bile acid synthesis and excretion. Reverse cholesterol transport, described as the transfer of cholesterol from non-hepatic cells, including foam cells in atherosclerotic plaques, to the liver and then its excretion in the feces is important part of this regulation. High-density lipoproteins are the key mediators of reverse cholesterol transport. On the other hand, microRNA-33 was identified as a key regulator of cholesterol homeostasis. Recent studies indicate the impact of microRNA-33 not only on cellular cholesterol efflux and HDL production but also on bile metabolism in the liver. As proper coordination of cholesterol metabolism is essential to human health, discussion of recent findings in this field may open new perspectives in the microRNA-dependent treatment of a cholesterol imbalance. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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32 pages, 1269 KiB

Open AccessReview

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

by Agostino Di Ciaula, Leonilde Bonfrate, Jacek Baj, Mohamad Khalil, Gabriella Garruti, Frans Stellaard, Helen H. Wang, David Q.-H. Wang and Piero Portincasa

Nutrients 2022, 14(23), 4950; https://doi.org/10.3390/nu14234950 - 22 Nov 2022

Cited by 27 | Viewed by 4359

Abstract

Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption [...] Read more.

Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/β-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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16 pages, 1522 KiB

Open AccessReview

Investigating microRNAs to Explain the Link between Cholesterol Metabolism and NAFLD in Humans: A Systematic Review

by Maurice C. J. M. Konings, Sabine Baumgartner, Ronald P. Mensink and Jogchum Plat

Nutrients 2022, 14(23), 4946; https://doi.org/10.3390/nu14234946 - 22 Nov 2022

Cited by 5 | Viewed by 2061

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by hepatic free cholesterol accumulation. In addition, microRNAs (miRNAs) might be involved in NAFLD development. Therefore, we systematically reviewed the literature to examine the link between miRNAs and cholesterol metabolism in NAFLD. Nineteen studies were retrieved [...] Read more.

Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by hepatic free cholesterol accumulation. In addition, microRNAs (miRNAs) might be involved in NAFLD development. Therefore, we systematically reviewed the literature to examine the link between miRNAs and cholesterol metabolism in NAFLD. Nineteen studies were retrieved by a systematic search in September 2022. From these papers, we evaluated associations between 13 miRNAs with NAFLD and cholesterol metabolism. Additionally, their diagnostic potential was examined. Four miRNAs (miR122, 34a, 132 and 21) were associated with cholesterol metabolism and markers for NAFLD. MiR122 was upregulated in serum of NAFLD patients, increased with disease severity and correlated with HDL-C, TAG, VLDL-C, AST, ALT, ALP, lobular inflammation, hepatocellular ballooning and NAFLD score. Serum and hepatic levels also correlated. Serum and hepatic miR34a levels were increased in NAFLD, and correlated with VLDL-C and TAG. Serum miR379 was also higher in NAFLD, especially in early stages, while miR21 gave ambiguous results. The diagnostic properties of these miRNAs were comparable to those of existing biomarkers. However, serum miR122 levels appeared to be elevated before increases in ALT and AST were evident. In conclusion, miR122, miR34a, miR21 and miR132 may play a role in the development of NAFLD via effects on cholesterol metabolism. Furthermore, it needs to be explored if miRNAs 122, 34a and 379 could be used as part of a panel in addition to established biomarkers in early detection of NAFLD. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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10 pages, 700 KiB

Open AccessReview

Is There a Correlation between Dietary and Blood Cholesterol? Evidence from Epidemiological Data and Clinical Interventions

by Maria Luz Fernandez and Ana Gabriela Murillo

Nutrients 2022, 14(10), 2168; https://doi.org/10.3390/nu14102168 - 23 May 2022

Cited by 18 | Viewed by 11008

Abstract

Dietary cholesterol has been a topic of debate since the 1960s when the first dietary guidelines that limited cholesterol intake to no more than 300 mg/day were set. These recommendations were followed for several years, and it was not until the late 1990s [...] Read more.

Dietary cholesterol has been a topic of debate since the 1960s when the first dietary guidelines that limited cholesterol intake to no more than 300 mg/day were set. These recommendations were followed for several years, and it was not until the late 1990s when they were finally challenged by the newer information derived from epidemiological studies and meta-analysis, which confirmed the lack of correlation between dietary and blood cholesterol. Further, dietary interventions in which challenges of cholesterol intake were evaluated in diverse populations not only confirmed these findings but also reported beneficial effects on plasma lipoprotein subfractions and size as well as increases in HDL cholesterol and in the functionality of HDL. In this review, we evaluate the evidence from recent epidemiological analysis and meta-analysis as well as clinical trials to have a better understanding of the lack of correlation between dietary and blood cholesterol. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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14 pages, 1466 KiB

Open AccessReview

From Dietary Cholesterol to Blood Cholesterol, Physiological Lipid Fluxes, and Cholesterol Homeostasis

by Frans Stellaard

Nutrients 2022, 14(8), 1643; https://doi.org/10.3390/nu14081643 - 14 Apr 2022

Cited by 31 | Viewed by 4790

Abstract

Dietary cholesterol (C) is a major contributor to the endogenous C pool, and it affects the serum concentration of total C, particularly the low-density lipoprotein cholesterol (LDL-C). A high serum concentration of LDL-C is associated with an increased risk for atherosclerosis and cardiovascular [...] Read more.

Dietary cholesterol (C) is a major contributor to the endogenous C pool, and it affects the serum concentration of total C, particularly the low-density lipoprotein cholesterol (LDL-C). A high serum concentration of LDL-C is associated with an increased risk for atherosclerosis and cardiovascular diseases. This concentration is dependent on hepatic C metabolism creating a balance between C input (absorption and synthesis) and C elimination (conversion to bile acids and fecal excretion). The daily C absorption rate is determined by dietary C intake, biliary C secretion, direct trans-intestinal C excretion (TICE), and the fractional C absorption rate. Hepatic C metabolism coordinates C fluxes entering the liver via chylomicron remnants (CMR), LDL, high-density lipoproteins (HDL), hepatic C synthesis, and those leaving the liver via very low-density lipoproteins (VLDL), biliary secretion, and bile acid synthesis. The knowns and the unknowns of this C homeostasis are discussed. Full article

(This article belongs to the Special Issue From Dietary Cholesterol to Blood Cholesterol)

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