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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.
Dysregulation of cholesterol metabolism represents one of the major risk factors for atherosclerotic cardiovascular disease (CVD). Oxidized cholesterol esters (oxCE) in low-density lipoprotein (LDL) have been implicated in CVD but the underlying mechanisms remain poorly defined. We use a targeted lipidomic approach to demonstrate that levels of oxCEs in human plasma are associated with different types of CVD and significantly elevated in patients with myocardial infarction. We synthesized a major endogenous cholesterol ester hydroperoxide (CEOOH), cholesteryl-13(cis, trans)-hydroperoxy-octadecadienoate (ch-13(c,t)-HpODE) and show that this endogenous compound significantly increases plasma cholesterol level in mice while decrease cholesterol levels in mouse liver and peritoneal macrophages, which is primarily due to the inhibition of cholesterol uptake in macrophages and liver. Further studies indicate that inhibition of cholesterol uptake by ch-13(c,t)-HpODE in macrophages is dependent on LXRα-IDOL-LDLR pathway, whereas inhibition on cholesterol levels in hepatocytes is dependent on LXRα and LDLR. Consistently, these effects on cholesterol levels by ch-13(c,t)-HpODE are diminished in LDLR or LXRα knockout mice. Together, our study provides evidence that elevated plasma cholesterol levels by CEOOHs are primarily due to the inhibition of cholesterol uptake in the liver and macrophages, which may play an important role in the pathogenesis of CVD.
The absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and nerves from PMP22 knock-out (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current-clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with both mRNA and protein levels of apolipoprotein E (apoE) and ATP-binding cassette transporter A1 (ABCA1) being highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the transporter to the cell membrane and diminished secretion of apoE. The absence of PMP22 also impaired ABCA1-mediated cholesterol efflux capacity. In nerves from ABCA1 KO mice, the expression of PMP22 was significantly elevated and the subcellular processing of the overproduced protein was aberrant. In wild-type samples, double immunolabeling identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane and the two proteins were coimmunoprecipitated from Schwann cell and nerve lysates. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein ABCA1.SIGNIFICANCE STATEMENT Understanding the subcellular events that underlie abnormal myelin formation in hereditary neuropathies is critical for advancing therapy development. Peripheral myelin protein 22 (PMP22) is an essential peripheral myelin protein because its genetic abnormalities account for ∼80% of hereditary neuropathies. Here, we demonstrate that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells' plasma membrane are altered and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay among PMP22, cholesterol, apolipoprotein E, and the major cholesterol-efflux transporter protein ATP-binding cassette transporter A1 (ABCA1). These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in Schwann cells.
ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux from cells and regulates intracellular cholesterol homeostasis. Here we demonstrate a role of ABCG1 as a mediator of tumour immunity. Abcg1(-/-) mice have dramatically suppressed subcutaneous MB49-bladder carcinoma and B16-melanoma growth and prolonged survival. We show that reduced tumour growth in Abcg1(-/-) mice is myeloid cell intrinsic and is associated with a phenotypic shift of the macrophages from a tumour-promoting M2 to a tumour-fighting M1 within the tumour. Abcg1(-/-) macrophages exhibit an intrinsic bias towards M1 polarization with increased NF-κB activation and direct cytotoxicity for tumour cells in vitro. Overall, our study demonstrates that the absence of ABCG1 inhibits tumour growth through modulation of macrophage function within the tumour, and illustrates a link between cholesterol homeostasis and cancer.
Bacterial adherence to tissues is a necessary step in infection and results from interactions between surface molecules on the bacteria (adhesins) and plasma membrane receptors on host cells. Using a clinical isolate of Pseudomonas aeruginosa, we have examined the receptors required for adherence to Chinese hamster ovary (CHO) cells. In mutant CHO cell lines and mucin-producing lung epithelial cell lines, adherence did not depend on glycoproteins, glycolipids, or proteoglycans. Treating cells with glutaraldehyde and proteases also did not affect adherence. However, treating cells with ethanol diminished adherence and resulted in removal of factors that would facilitate binding of bacteria when coated on plastic culture plates. These factors were purified by solvent extraction and silica gel chromatography and were identified as cholesterol and cholesterol esters by coelution with authentic standards, gas chromatography, 1H NMR, and mass spectrometry. Bacterial adherence was reduced to wild-type CHO cells treated with Lovastatin and to cholesterol-requiring insect cells grown in cholesterol-deficient medium, suggesting that the bacteria bound to plasma membrane cholesterol. Thus, this clinical isolate of Pseudomonas uses cholesterol and cholesterol esters for adherence. We propose that binding to cholesterol and cholesterol esters may affect the pathogenicity of similar Pseudomonas strains.
The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a clade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health.
Cells use various mechanisms to maintain cellular cholesterol homeostasis including efflux of cholesterol from the cellular plasma membrane to cholesterol acceptors such as HDLs (high-density lipoproteins). Little is known about the transfer of cholesterol from cells into the extracellular matrix. Using a unique monoclonal antibody that detects ordered cholesterol arrays (ie, cholesterol micro[or nano]-domains), we previously identified that particles containing these cholesterol domains accumulate in the extracellular matrix during cholesterol enrichment of human monocyte-derived macrophages and are found in atherosclerotic lesions. In this study, we further investigate these deposited particles containing cholesterol microdomains and discover their unexpected morphology.
LAMP1 and LAMP2 proteins are highly abundant, ubiquitous, mammalian proteins that line the lysosome limiting membrane, and protect it from lysosomal hydrolase action. LAMP2 deficiency causes Danon's disease, an X-linked hypertrophic cardiomyopathy. LAMP2 is needed for chaperone-mediated autophagy, and its expression improves tissue function in models of aging. We show here that human LAMP1 and LAMP2 bind cholesterol in a manner that buries the cholesterol 3β-hydroxyl group; they also bind tightly to NPC1 and NPC2 proteins that export cholesterol from lysosomes. Quantitation of cellular LAMP2 and NPC1 protein levels suggest that LAMP proteins represent a significant cholesterol binding site at the lysosome limiting membrane, and may signal cholesterol availability. Functional rescue experiments show that the ability of human LAMP2 to facilitate cholesterol export from lysosomes relies on its ability to bind cholesterol directly.
To examine the ability of total cholesterol (TC), a low-density lipoprotein cholesterol (LDL-C) proxy widely used in public health initiatives, to capture important population-level shifts away from ideal and intermediate LDL-C throughout adulthood. We estimated age (≥20 years)-, race/ethnic (Caucasian, African American, and Hispanic/Latino)-, and sex- specific net transition probabilities between ideal, intermediate, and poor TC and LDL-C using National Health and Nutrition Examination Survey (2007-2014; N = 13,584) and Hispanic Community Health Study/Study of Latinos (2008-2011; N = 15,612) data in 2016 and validated and calibrated novel Markov-type models designed for cross-sectional data. At age 20, >80% of participants had ideal TC, whereas the race/ethnic- and sex-specific prevalence of ideal LDL-C ranged from 39.2%-59.6%. Net transition estimates suggested that the largest one-year net shifts away from ideal and intermediate LDL-C occurred approximately two decades earlier than peak net population shifts away from ideal and intermediate TC. Public health and clinical initiatives focused on monitoring TC in middle-adulthood may miss important shifts away from ideal and intermediate LDL-C, potentially increasing the duration, perhaps by decades, that large segments of the population are exposed to suboptimal LDL-C.
The present study aimed to investigate the antihypercholesterolemic effects of krill oil supplementation in high-cholesterol diet-induced hypercholesterolemic rats, and the mechanisms underlying these effects. Rats were divided into five groups: normal control, control (high-cholesterol diet), krill oil 100 mg/kg b.w. (high-cholesterol diet with Krill oil 100 mg/kg b.w.), and krill oil 200 mg/kg b.w. (high-cholesterol diet with Krill oil 200 mg/kg b.w.). After 12 weeks, the rats were sacrificed to observe the effects of krill oil on cholesterol synthesis and excretion. We found that krill oil supplementation suppressed total triglycerides, total cholesterol, and LDL-cholesterol levels, as well as HMG-CoA reductase activity. It stimulated AMPK phosphorylation, LDL receptor and ACAT2 expression in the liver, and the fecal output of cholesterol. Furthermore, it decreased the levels of P-selectin, sVCAM-1, and NO, as well as aortic wall thickness, demonstrating its role in the prevention of atherosclerosis. Thus, we suggest that krill oil supplementation can reduce LDL-cholesterol levels in the blood during hypercholesterolemia by stimulating the uptake of LDL-cholesterol into tissue and cholesterol excretion, as well as inhibition of cholesterol synthesis.
Although cholesterol-rich microdomains are highly involved in the functions of cardiomyocytes, the cholesterol homeostasis is largely unknown in these cells. We developed experimental procedures to assess cholesterol synthesis, cholesterol masses and cholesterol efflux from primary cultures of cardiac myocytes obtained from 2 to 4 days old Wistar rats. We first observed that cardiomyocytes poorly internalized exogenously supplied native or modified LDL and that free cholesterol (FC) efflux to free apolipoprotein AI (apo AI) and to HDL was mediated by ATP binding cassette transporter A1 (ABCA1) and likely by ATP binding cassette transporter G1 (ABCG1), respectively, which are both upregulated by liver X receptor/retinoid X receptor (LXR/RXR) activation. We then investigated the consequences of cholesterol synthesis inhibition on cholesterol homeostasis using an HMGCoA reductase inhibitor (pravastatin, 90% effective concentration (EC90): 0.11 mM, 18 h). We observed no impact of cholesterol synthesis inhibition on the FC or cholesteryl ester (CE) masses. Consistently with no FC mass changes, pravastatin treatment had no notable impact on LDL receptors mRNA expression or on the capacity of cardiomyocytes to uptake radiolabeled LDL. Conversely, pravastatin treatment induced a significant decrease of cholesterol efflux to both apo AI and HDL whereas the passive aqueous diffusion remained unchanged. The cholesterol efflux pathway reductions induced by cholesterol synthesis inhibition were not caused by a reduction of ABC transporter expression (mRNA or protein). These results show that cardiac myocytes down-regulate active cholesterol efflux processes when endogenous cholesterol synthesis is inhibited, allowing them to preserve cholesterol homeostasis.
1. We administered the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin at a daily dose of 1 mg kg(-1) body weight to cholesterol-fed (0.03%) heterozygous Watanabe heritable hyperlipidaemic rabbits, an animal model for heterozygous familial hypercholesterolaemia. 2. After 12 months of cholesterol treatment, immunohistochemistry with the monoclonal antibody 9D9 was used to detect hepatic low density lipoprotein (LDL) receptors, which were quantified by densitometry. In addition we determined LDL receptor mRNA by competitive reverse transcriptase polymerase chain reaction. The cholesterol precursor lathosterol and the plant sterol campesterol were analysed by gas-liquid chromatography. 3. The drug reduced total plasma cholesterol levels by 51% (P=0.04), when compared to the control group. Unexpectedly, hepatic LDL receptor density and mRNA showed no significant differences between the groups. Total plasma levels of lathosterol and campesterol also revealed no significant differences between the groups, if expressed relative to plasma cholesterol. 4. The findings suggest that mechanisms other than induced hepatic LDL receptors are responsible for the cholesterol-lowering effect of pravastatin in this animal model. We propose a reduced cholesterol absorption efficiency compatible with similar campesterol levels between both groups observed in our study.
Deliberate and regular exposure to premium motor spirit fumes is common and could be a risk factor for liver disease in those who are occupationally exposed. A possible association between premium motor spirit fumes and plasma levels of triglyceride, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol using a rodent model could provide new insights in the pathology of diseases where cellular dysfunction is an established risk factor.
Current guidelines suggest screening for dyslipidemia in early adulthood. In Thailand, a screening total cholesterol level is most commonly used potentially due to the costs of the test. However, the appropriate TC cut-off point that correlates with elevated low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (Non-HDL-C) levels for the low cardiovascular risk younger population have not been examined extensively in the literature.
There are indications for tracking of circulating total cholesterol concentration (TC) from childhood to later in life. An increased lifelong TC exposure increases the risk of developing atherosclerosis, however little is known about the determinants of TC early in life. We aimed to describe TC in Norwegian offspring aged 6, 12 and 24 months, and to explore if maternal TC, breastfeeding and offspring diet are associated with offspring TC.
Achilles tendon xanthoma (ATX) formation involves macrophage cholesterol accumulation within the tendon, similar to that occurring in atheroma. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, namely the high-density lipoprotein (HDL) capacity to promote cell cholesterol efflux (cholesterol efflux capacity, CEC) and the serum cholesterol loading capacity (CLC). We explored the HDL-CEC and serum CLC, comparing 16 FH patients with ATX to 29 FH patients without ATX. HDL-CEC through the main efflux mechanisms mediated by the transporters ATP binding cassette G1 (ABCG1) and A1 (ABCA1) and the aqueous diffusion (AD) process was determined by a cell-based radioisotopic technique and serum CLC fluorimetrically. Between the two groups, no significant differences were found in terms of plasma lipid profile. A trend toward reduction of cholesterol efflux via AD and a significant increase in ABCA1-mediated HDL-CEC (+18.6%) was observed in ATX compared to no ATX patients. In ATX-presenting patients, ABCG1-mediated HDL-CEC was lower (−11%) and serum CLC was higher (+14%) compared to patients without ATX. Considering all the patients together, ABCG1 HDL-CEC and serum CLC correlated with ATX thickness inversely (p = 0.013) and directly (p < 0.0001), respectively. In conclusion, lipoprotein dysfunctions seem to be involved in ATX physiopathology and progression in FH patients.
When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? In this study, we define three pools of PM cholesterol: (1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; (2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and (3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the ER's PFO-accessible regulatory pool. This regulatory mechanism allows cells to ensure optimal cholesterol levels in PM while avoiding cholesterol overaccumulation.
We evaluated the effect of cacao procyanidins (CP) on plasma lipid levels in high cholesterol-fed rats. Animals were divided into 4 groups, and each group was fed on either a normal diet, high cholesterol diet (HCD) containing 1% cholesterol (HCD without CP), HCD with 0.5% (HCD with 0.5% CP) or 1.0% CP (HCD with 1.0% CP) for 4 weeks. Plasma cholesterol level was significantly higher in the HCD without CP group than the normal diet group (p<0.01). Supplementation of CP significantly decreased plasma cholesterol (p<0.01) to levels similar to those of the normal diet group. The liver cholesterol and triglyceride levels in all HCD groups were significantly higher (p<0.01), but 1.0% CP feeding significantly reduced this increase. Fecal excretion of neutral sterol and triglyceride was significantly increased in all HCD groups (p<0.01), and the excreted amounts tended to be higher in the HCD with CP groups. The procyanidins dose-dependently reduced micellar solubility of cholesterol and this activity increased with increasing molecular weight. These results suggest that one of the mechanisms of CP to lower plasma cholesterol is inhibition of intestinal absorption of cholesterol.
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