Absorption Of Dietary Cholesterol Research Articles

Cholesin and GPR146 in Modulating Cholesterol Biosynthesis.

Cholesterol homeostasis in the human body is a crucial process that involves a delicate balance between dietary cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver. Both pathways contribute significantly to the overall pool of cholesterol in the body, influencing plasma cholesterol levels and impacting cardiovascular health. Elevated absorption of cholesterol in the intestines has a suppressive impact on the synthesis of cholesterol in the liver, serving to preserve cholesterol balance. Nonetheless, the precise mechanisms driving this phenomenon remain largely unclear. This review aimed to discuss the previously unrecognized role of cholesin and GPR146 in the regulation of cholesterol biosynthesis, providing a novel conceptual framework for understanding cholesterol homeostasis. The discovery of cholesin, a novel protein implicated in the regulation of cholesterol homeostasis, represents a significant advancement in our understanding of cholesterol biosynthesis and its associated pathways. The cholesin-GPR146 axis could have profound implications across various therapeutic areas concerning abnormal cholesterol metabolism, offering new hope for patients and improving overall healthcare outcomes.

Abstract 2004: Sex Differences In Bile Acid Metabolism Impact Cholesterol Homeostasis And Cardiovascular Disease

Cardiovascular disease (CVD) remains the leading cause of death in the United States for both men and women, despite cholesterol-lowering drugs such as statins. Diets rich in cholesterol are well-known to contribute to disease progression. The absorption of dietary cholesterol is facilitated by liver-synthesized detergents called bile acids. We hypothesized that manipulating bile acid metabolism to reduce cholesterol absorption would result in decreased plasma cholesterol levels and protect from atherosclerosis. To alter the bile acid pool, we used liver-directed AAV-CRISPR to disrupt Cyp7a1, which catalyzes the rate-limiting step of bile acid synthesis. Consequently, we show that loss of CYP7A1 in adult male mice reduces the size of the bile acid pool. To study atherosclerosis, we co-disrupted Cyp7a1 concurrently with Low Density Lipoprotein Receptor ( Ldlr ) to induce hypercholesterolemia on a Western diet for 20 weeks. Loss of hepatic CYP7A1 in males reduced atherosclerosis and reduced cholesterol absorption. In stark contrast to what we observed in male mice, the absence of this rate limiting enzyme in female mice resulted in only a modest reduction in the bile acid pool. This blunted reduction in bile acids in female Cyp7a1 CRISPR mice was not sufficient to decrease cholesterol absorption, resulting in accumulation of cholesterol, and consequently increasing cardiovascular risk. We hypothesize that there is a female-specific mechanism to preserve bile acid production that operates in the absence of CYP7A1. We are currently in the process of testing candidate female-specific enzymes for bile acid production. These studies indicate new avenues by which female bile acid and cholesterol metabolism regulation differs from than that of males. The resulting differences in cardiovascular risk highlight the essential need for male- and female-specific personalized medicine approaches for cardiovascular disease prevention.

Associations of Dietary Cholesterol Consumption With Incident Diabetes and Cardiovascular Disease: The Role of Genetic Variability in Cholesterol Absorption and Disease Predisposition.

Whether genetic susceptibility to disease and dietary cholesterol (DC) absorption contribute to inconsistent associations of DC consumption with diabetes and cardiovascular disease (CVD) remains unclear. DC consumption was assessed by repeated 24-h dietary recalls in the UK Biobank. A polygenetic risk score (PRS) for DC absorption was constructed using genetic variants in the Niemann-Pick C1-Like 1 and ATP Binding Cassettes G5 and G8 genes. PRSs for diabetes, coronary artery disease, and stroke were also created. The associations of DC consumption with incident diabetes (n = 96,826) and CVD (n = 94,536) in the overall sample and by PRS subgroups were evaluated using adjusted Cox models. Each additional 300 mg/day of DC consumption was associated with incident diabetes (hazard ratio [HR], 1.17 [95% CI, 1.07-1.27]) and CVD (HR, 1.09 [95% CI, 1.03-1.17]), but further adjusting for BMI nullified these associations (HR for diabetes, 0.99 [95% CI, 0.90-1.09]; HR for CVD, 1.04 [95% CI, 0.98-1.12]). Genetic susceptibility to the diseases did not modify these associations (P for interaction ≥0.06). The DC-CVD association appeared to be stronger in people with greater genetic susceptibility to cholesterol absorption assessed by the non-high-density lipoprotein cholesterol-related PRS (P for interaction = 0.04), but the stratum-level association estimates were not statistically significant. DC consumption was not associated with incident diabetes and CVD, after adjusting for BMI, in the overall sample and in subgroups stratified by genetic predisposition to cholesterol absorption and the diseases. Nevertheless, whether genetic predisposition to cholesterol absorption modifies the DC-CVD association requires further investigation.

Treatment of Ezetimibe lowers total and low-density lipoprotein cholesterol in hypercholesterolemic dogs with hyperadorenocorticism.

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol, thereby lowering primarily low density lipoprotein-cholesterol (LDL-chol) in human studies. This study aimed to investigate the effects of ezetimibe on dyslipidemia control in nine dogs with hypercholesterolemia. Changes in total cholesterol (T-chol) and each lipoprotein fractions were evaluated at 0, 2, and 4 months following initiation of ezetimibe treatment. A significant decrease in T-chol was observed, and a mean T-chol concentration below 400 mg/dL was achieved at 2 and 4 months. Furthermore, a significant decrease in LDL-chol was observed (-53.3% and -64.3% at 2 and 4 months, respectively). Taken together, treatment of ezetimibe could lower LDL-chol levels in dogs with hypercholesterolemia.

New insights into dietary cholesterol absorption.

New insights into dietary cholesterol absorption.

Cholic acid increases plasma cholesterol in Smith-Lemli-Opitz syndrome: A pilot study

BackgroundSmith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol biosynthesis associated with congenital malformations, growth delay, intellectual disability and behavior problems. SLOS is caused by bi-allelic mutations in DHCR7, which lead to reduced activity of 7-dehydrocholesterol reductase that catalyzes the last step in cholesterol biosynthesis. Symptoms of SLOS are thought to be due to cholesterol deficiency and accumulation of its precursor 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC), and toxic oxysterols. Therapy for SLOS often includes dietary cholesterol supplementation, but lipids are poorly absorbed from the diet, possibly due to impaired bile acid synthesis. We hypothesized that bile acid supplementation with cholic acid would improve dietary cholesterol absorption and raise plasma cholesterol levels. MethodsTwelve SLOS subjects (10 M, 2F, ages 2–27 years) who had plasma cholesterol ≤125 mg/dL were treated with cholic acid (10 mg/kg/day) divided twice daily for 2 months. Plasma cholesterol, 7-DHC and 8-DHC were measured by GC–MS. Oxysterols were measured by ultra-high-performance LC-MS/MS. Data were analyzed using paired t-tests. ResultsAt baseline, plasma cholesterol was 75 ± 24 mg/dL (mean ± SD; range 43–125, n = 12). After 2 months on cholic acid, mean plasma cholesterol increased to 97 ± 29 mg/dL (p = 0.011). Eleven of 12 subjects showed an increase in plasma cholesterol that varied from 3.8% to 85.7% (mean 38.7 ± 23.3%). 7-Hydroxycholesterol decreased by 20.6% on average (p = 0.013) but no significant changes were seen in 7-DHC or 8-DHC. Mean body weight tended to increase (3.6% p = 0.069). Subjects tolerated cholic acid well and experienced no drug-related adverse events. ConclusionsIn this pilot study, cholic acid supplementation was well tolerated and safe and resulted in an increase in plasma cholesterol in most SLOS subjects. Further controlled longitudinal studies are needed to look for the sustainability of the biochemical effect and possible clinical benefits.

Cholesterol solubilization: Interplay between phytosterols, saponins and lipid digestion products

High plasma concentrations of cholesterol are associated with cardio-vascular disease complications and high risk of myocardial infarction. The absorption of dietary cholesterol depends on its bioaccessibility, which is in turn influenced by phytosterols, saponins and lipid digestion products. Therefore, we explored the interplay between phytosterols, Quillaja Dry saponin extract (QD), their combinations and lipid digestion on cholesterol bioaccessibility via an in vitro.

An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells.

Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection.

Could Lowering Phytosterol Absorption as Part of Lipid-Lowering Therapy Have a Beneficial Effect on Residual Risk?

Plant sterols are molecules that are structurally similar to cholesterol and provided only as dietary sources (e.g., vegetables, fruits, nuts, cereals) since they cannot be synthesized by humans. Sterol-enriched diets (≥2 g/day) may decrease total and low-density lipoprotein cholesterol concentrations by 5-10%, either alone or when added to statins, since they antagonize dietary cholesterol absorption in the intestine. On the other hand, increased serum phytosterol concentrations, (including when associated with sitosterolemia, a rare genetic defect) may contribute to atherosclerotic risk, although a threshold for such a role has not been established. Medications such as ezetimibe may effectively reduce cholesterol and phytosterol absorption. Whether the therapeutic approach associated with the reduction of phytosterol absorption is also translated into a reduction in a patient's residual cardiovascular risk needs to be established.

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

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.

ODP152 Impact of Dietary Cholesterol on LDL: Lessons in Absorption and Overconsumption

Abstract Background The impact of dietary cholesterol on lipid profiles have remained controversial, highlighted by alterations in the 2015-2020 American Heart Association dietary guidelines abolishing the prior dietary cholesterol limit of 300mg/day. Eggs often are the example cited in this debate as they are a rich source of dietary cholesterol without comparative high levels of saturated fat, 1 of which the effects on LDL cholesterol are well established. To date, evidence has been mixed although most studies show only modest increases in LDL with dietary cholesterol. 1 However, recent research supports significant variation in these findings among predisposed individuals. 2 Heterogeneity in dietary cholesterol absorption can potentially account for these variations and has important clinical implications. Clinical Case A 58 year old woman with PMH ulcerative colitis, hyperlipidemia, and radiological evidence of CAD without prior CVD, presented for management of hyperlipidemia. At baseline, her lipid panel in 2015 noted an LDL-C of 125 mg/dL. In 2017, LDL-C was 255 mg/dL, prompting treatment with Atorvastatin. Following initiation of Atorvastatin, LDL-C improved to 137 mg/dL. However, on Atorvastatin, she experienced dermatitis and underwent Dermatology evaluation/biopsy. Medication reaction was favored as the etiology and Atorvastatin was discontinued. In Jan. 2019, off of Atorvastatin, LDL-C was 162 mg/dL. From around 2015-2018, the patient consumed a vegan diet. In 2019, she incorporated nine eggs per day (1600mg dietary cholesterol) into her diet. She denied additional changes to diet or consumption of other animal products. In Aug. 2019, LDL-C was 378 mg/dL. In Aug. 2020, LDL-C was 420 mg/dL. In Aug. 2020, she was advised that her goal LDL was 100 mg/dL or less. She was advised to limit her egg yolk consumption to four per week (∼100 mg/day of cholesterol). She continued to avoid all other animal products. In Oct. 2020, without addition of medication or other notable lifestyle changes her LDL-C decreased to 204 mg/dL. In Jan. 2021, her LDL-C was 130 mg/dL. From 2015-2021, her weight ranged 93-103lbs (BMI ∼16). In Aug. 2021, her LDL-C was 142 mg/dL. Ezetimibe 10mg daily was then added with reduction in LDL-C to a near-target of 103 mg/dL (27% reduction) within four months. Conclusion For the average American, current guidelines do not recommend egg restriction as an effective tool for LDL-C lowering. However, as shown in this case, certain individuals may be more prone to high LDL-C when consuming high cholesterol diets. Further study on how to better identify these susceptible individuals could help personalize nutritional and medication treatment plans for patients with dyslipidemia.

Making a meal out of bugs

Making a meal out of bugs

Flaxseed-derived peptide, IPPF, inhibits intestinal cholesterol absorption in Caco-2 cells and hepatic cholesterol synthesis in HepG2 cells.

Flaxseed peptides reduced serum cholesterol levels in Sprague-Dawley rats fed with a high-cholesterol diet. However, the mechanism of this action remains unclear. Flaxseed-hydrolyzed proteins were separated through ultrafiltration. The fifth fraction (FP5 , ≤ 1kDa) had the highest cholesterol micelle solubility inhibition rate (CMSR) of 72.39% among the other fractions. Eleven peptides were identified from FP5 . Ile-Pro-Pro-Phe (IPPF), which had the highest CMSR of 93.47%, was selected for further analyses. IPPF substantially reduced the cholesterol transported content in Caco-2 cells and the total cholesterol content in HepG2 cells. Moreover, IPPF modulated the protein levels of NCP1L1 and ABCG5/8 (cholesterol transporters) in Caco-2 cells and reduced the mRNA levels of Srebp-2 and Hmgcr (cholesterol synthesis enzymes) in HepG2 cells. IPPF inhibits cholesterol intestinal absorption by modulating the cholesterol transporters expression and reduces hepatic cholesterol synthesis by inhibiting the SREBP2-regulated mevalonate pathway. IPPF is a new food-derived cholesterol-lowering nutritional supplement. PRACTICAL APPLICATIONS: We isolated active peptides with cholesterol-lowering properties from flaxseed protein, a by-product of industrial oil production, which greatly improved the economic and medicinal value of flaxseed protein. According to our research, IPPF can be used as a new food-derived type of cholesterol intestinal absorption inhibitor to reduce dietary cholesterol absorption and cholesterol synthesis inhibitor (same pharmacological mechanism as statins). IPPF provide a nutritional therapy component for hypercholesterolemia and prevent atherosclerosis. Our research provides theoretical basis for development and utilization of new nutritional supplements and plant proteins.

Interfering with cholesterol metabolism impairs tick embryo development and turns eggs susceptible to bacterial colonization

Cholesterol is a known precursor of arthropod molecules such as the hormone 20-hydroxyecdysone and the antimicrobial boophiline, a component of tick egg wax coat. Because the cholesterol biosynthetic pathway is absent in ticks, it is necessarily obtained from the blood meal, in a still poorly understood process. In contrast, dietary cholesterol absorption is better studied in insects, and many proteins are involved in its metabolism, including Niemann-Pick C (NPC) transporter and acyl-CoA:cholesterol acyltransferase (ACAT), as well as enzymes to convert between free cholesterol and esterified cholesterol. The present work addresses the hypothesis that tick viability can be impaired by interfering with cholesterol metabolism, proposing this route as a target for novel tick control methods. Two drugs, ezetimibe (NPC inhibitor) and avasimibe (ACAT inhibitor) were added to calf blood and used to artificially feed Rhipicephalus microplus females. Results show that, after ingesting avasimibe, tick reproductive ability and egg development are impaired. Also, eggs laid by females fed with avasimibe did not hatch and were susceptible to Pseudomonas aeruginosa adhesion and biofilm formation in their surfaces. The immunoprotective potential of ACAT against ticks was also accessed using two selected ACAT peptides. Antibodies against these peptides were used to artificially feed female ticks, but no deleterious effects were observed. Taken together, data presented here support the hypothesis that enzymes and other proteins involved in cholesterol metabolism are suitable as targets for tick control methods.

Obesity Does Not Interfere with the Cholesterol-Lowering Effect of Plant Stanol Ester Consumption (as Part of a Heart-Healthy Diet).

Dietary modifications including plant stanol ester consumption are recommended measures to control serum and low-density lipoprotein (LDL)-cholesterol concentrations, but obesity can affect their responses. We investigated whether body mass index (BMI) affects serum cholesterol levels during plant stanol (mainly sitostanol) ester consumption. This ad hoc analysis was based on earlier results of a cross-over, randomized controlled trial of postmenopausal women consuming rapeseed oil-based margarine without or with plant stanol ester (3 g plant stanols/day) for seven weeks. We classified the subjects as normal-weight (BMI ≤ 25 kg/m2, n = 9, mean 22.6 kg/m2) or overweight/obese (BMI > 25 kg/m2, n = 11, mean 28.4 kg/m2), and recalculated the results, focusing on cholesterol absorption, cholesterol synthesis, and fecal steroid outputs. Serum cholesterol levels were similar in the groups during the control diet. Plant stanol ester reduced serum cholesterol by 0.63 ± 0.19 mmol/L (11%) in normal-weight and by 0.75 ± 0.13 mmol/L (12%) in overweight/obese subjects (p < 0.05 for both), and cholesterol absorption was reduced in both groups. However, relative and dietary cholesterol absorption were more effectively reduced in normal-weight subjects. In conclusion, overweight/obesity did not interfere with the serum cholesterol response to plant stanol ester consumption despite substantial differences in cholesterol metabolism between the groups.

The Fate of Dietary Cholesterol in the Kissing Bug Rhodnius prolixus.

Insects are unable to synthesize cholesterol and depend on the presence of sterols in the diet for cell membrane composition and hormone production. Thus, cholesterol absorption, transport, and metabolism are potential targets for vector and pest control strategies. Here, we investigate the dietary cholesterol absorption and tissue distribution in the kissing bug Rhodnius prolixus using radiolabeled cholesterol. Both the anterior and posterior midguts absorbed cholesterol from the ingested blood, although the anterior midgut absorbed more. We also observed esterified cholesterol labeling in the epithelium, indicating that midgut cells can metabolize and store cholesterol. Only a small amount of labeled cholesterol was found in the hemolymph, where it was mainly in the free form and associated with lipophorin (Lp). The fat body transiently accumulated cholesterol, showing a labeled cholesterol peak on the fifth day after the blood meal. The ovaries also incorporated cholesterol, but cumulatively. The insects did not absorb almost half of the ingested labeled cholesterol, and radioactivity was present in the feces. After injection of 3H-cholesterol-labeled Lp into females, a half-life of 5.5 ± 0.7 h in the hemolymph was determined. Both the fat body and ovaries incorporated Lp-associated cholesterol, which was inhibited at low temperature, indicating the participation of active cholesterol transport. These results help describe an unexplored part of R. prolixus lipid metabolism.

CHOLESTEROL AND ITS IMPLICATIONS- A REVIEW

Ambiguity associated with cholesterol portrays its significance and concern. Cholesterol is a steroid biomolecule of animal cells with several important functions in living system, such as steroid hormone production, structural architecture of cell membranes, production of vitamin D, sources of bile salts and bile acids. Its sources include endogenous (de novo production by body’s tissues) and exogenous (dietary), contributing to cholesterol pool in the body. Cholesterol homeostasis is essentially regulated by the body. This review focuses on the following; basis of cholesterol, biological functions of cholesterol, structural description of cholesterol, Biosynthesis of cholesterol, cholesterol and its derivatives e.g bile acids, bile salts, steroid hormone, absorption and utilization of dietary cholesterol and current advancement in cholesterol management against risk factors. Hypercholesterolaemia is known to be an important precondition to the etiology of cardiovascular disorders which include atherosclerosis, stroke and coronary heart diseases. Interventions for the management and prevention of hypercholesterolaemia currently advocated include pharmaceuticals (drugs) and non pharmaceuticals, but more concern on non pharmacological therapeutic interventions such as the use of Medicinal Plants and herbs, Nutraceuticals, Diet and Exercises (lifestyle) and Functional and Mediterranean Foods. It is thus glaring that the disease linked implication of cholesterol can be prevented and managed using the appropriate interventions.&#x0D; &#x0D; Peer Review History: &#x0D; Received 4 November 2020; Revised 12 Decembe; Accepted 2 January, Available online 15 January 2021&#x0D; UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.&#x0D; Received file: Comments of reviewer(s): &#x0D; Average Peer review marks at initial stage: 6.0/10&#x0D; Average Peer review marks at publication stage: 8.0/10&#x0D; Reviewer(s) detail:&#x0D; Dr. Rawaa Souhil Al-Kayali, Aleppo University, Syria, rawah67@hotmail.com&#x0D; Dr. U. S. Mahadeva Rao, Universiti Sultan Zainal Abidin, Terengganu Malaysia, raousm@gmail.com&#x0D; Similar Articles:&#x0D; USE OF DIOSGENIN, YAMOGENIN, TIGOGENIN AND NEOTIGOGENIN FOR TREATMENT OF HYPERLIPIDEMIA BY INHIBITING CHOLESTEROL ABSORPTION IN GIT &#x0D;

Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease.

AimsTo explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols.Methods and resultsWe examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75–2.31, P = 9.8 × 10−23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49–1.59, P = 1.1 × 10−154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10−4).ConclusionsGenetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.

Dietary caffeic acid, ferulic acid and coumaric acid supplements on cholesterol metabolism and antioxidant activity in rats

This study was designed to test the lipid-lowering and antioxidative activities of three phenolic compounds, caffeic acid, ferulic acid and coumaric acid. Four groups of rats were given a semisynthetic diet containing 3% of cholesterol for 6 weeks. The control group only received a high cholesterol diet, whereas the other three groups received a diet including 0.2% of caffeic acid, 0.2% of ferulic acid and 0.2% of coumaric acid. The caffeic acid, ferulic acid and coumaric acid significantly lowered the plasma lipid and hepatic cholesterol levels compared to those in the control (p < 0.05). The hepatic HMG-CoA reductase activity was significantly lower in the caffeic acid group than in the ferulic acid and coumaric acid groups (p < 0.05), while the hepatic ACAT activity was significantly lower in the caffeic acid, ferulic acid and coumaric acid groups compared to the control group (p < 0.05). The overall potential of the antioxidant system was significantly enhanced by the caffeic acid, ferulic acid and coumaric acid supplements as the plasma and hepatic TBARS levels were lowered while the hepatic SOD activities and GSH concentration were elevated in the high-cholesterol-fed rats (p < 0.05). Furthermore, these results indicated that the supplementation of caffeic acid, ferulic acid and coumaric acid boosted the antioxidant activity in rats and promoted the excretion of neutral sterol and acidic sterol (p < 0.05), thereby leading to a decreased absorption of dietary cholesterol as well as lower plasma, hepatic cholesterol and promoted excretion of fecal sterols.

Selective Ah receptor modulators attenuate NPC1L1-mediated cholesterol uptake through repression of SREBP-2 transcriptional activity

The ability of the aryl hydrocarbon receptor (AHR) to alter hepatic expression of cholesterol synthesis genes in a DRE-independent manner in mice and humans has been reported. We have examined the influence of functionally distinct classes of AHR ligands on the levels of Niemann–Pick C1-like intracellular cholesterol transporter (NPC1L1) and enzymes involved in the cholesterol synthesis pathway. NPC1L1 is known to mediate the intestinal absorption of dietary cholesterol and is clinically targeted. AHR ligands were capable of attenuating cholesterol uptake through repression of NPC1L1 expression. Through mutagenesis experiments targeting the two DRE sequences present in the promoter region of the NPC1L1 gene, we provide evidence that the repression does not require functional DRE sequences; while knockdown experiments demonstrated that this regulation is dependent on AHR and sterol-regulatory element-binding protein-2 (SREBP-2). Furthermore, upon ligand activation of AHR, the human intestinal Caco-2 cell line revealed coordinate repression of both mRNA and protein levels for a number of the cholesterol biosynthetic enzymes. Transcription of NPC1L1 and genes of the cholesterol synthesis pathway is predominantly regulated by SREBP-2, especially after treatment with a statin. Immunoblot analyses revealed a significant decrease in transcriptionally active SREBP-2 levels upon ligand treatment, whereas the precursor form of SREBP-2 was modestly increased by AHR activation. Mechanistic insights indicate that AHR induces proteolytic degradation of mature SREBP-2 in a calcium-dependent manner, which correlates with the AHR ligand-mediated upregulation of the transient receptor potential cation channel subfamily V member 6 (TRPV6) gene encoding for a membrane calcium channel. These observations emphasize a role for AHR in the systemic homeostatic regulation of cholesterol synthesis and absorption, indicating the potential use of this receptor as a target for the treatment of hyperlipidosis-associated metabolic diseases.