Role Of Cholesterol Research Articles

Beyond the classic GPCR: unraveling the role of GPR155 role in cholesterol sensing and signaling

Beyond the classic GPCR: unraveling the role of GPR155 role in cholesterol sensing and signaling

The Role of Cholesterol in M2 Clustering and Viral Budding Explained.

The influenza A M2 homotetrameric channel consists of four transmembrane (TM) and four amphipathic helices (AHs). This viral proton channel is suggested to form clusters in the catenoid budding neck areas in raft-like domains of the plasma membrane, resulting in cell membrane scission and viral release. The channel clustering environment is rich in cholesterol. Previous experiments have shown that cholesterol significantly contributes to lipid bilayer undulations in viral buds. However, a clear explanation of membrane curvature from the distribution of cholesterol around the M2TM-AH clusters is lacking. Using coarse-grained molecular dynamics simulations of M2TM-AH in bilayers, we observed that M2 channels form specific, C2-symmetric, clusters with conical shapes driven by the attraction of their AHs. We showed that cholesterol stabilized the formation of M2 channel clusters by filling and bridging the conical gap between M2 channels at specific sites in the N-termini of adjacent channels or via the C-terminal region of TM and AHs, with the latter sites displaying a longer interaction time and higher stability. The potential of mean force calculations showed that when cholesterols occupy the identified interfacial binding sites between two M2 channels, the dimer is stabilized by 11 kJ/mol. This translates to the cholesterol-bound dimer being populated by almost 2 orders of magnitude compared to a dimer lacking cholesterol. We demonstrated that the cholesterol-bridged M2 channels can exert a lateral force on the surrounding membrane to induce the necessary negative Gaussian curvature profile, which permits spontaneous scission of the catenoid membrane neck and leads to viral buds and scission.

Role of cholesterol in modulating brain hyperexcitability.

Cholesterol is a critical molecule in the central nervous system, and imbalances in the synthesis and metabolism of brain cholesterol can result in a range of pathologies, including those related to hyperexcitability. The impact of cholesterol on disorders of epilepsy and developmental and epileptic encephalopathies is an area of growing interest. Cholesterol cannot cross the blood-brain barrier, and thus the brain synthesizes and metabolizes its own pool of cholesterol. The primary metabolic enzyme for brain cholesterol is cholesterol 24-hydroxylase (CH24H), which metabolizes cholesterol into 24S-hydroxycholesterol (24HC). Dysregulation of CH24H and 24HC can affect neuronal excitability through a range of mechanisms. 24HC is a positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors and can increase glutamate release via tumor necrosis factor-α-dependent pathways. Increasing cholesterol metabolism can lead to dysfunction of excitatory amino acid transporter 2 and impair glutamate reuptake. Finally, overstimulation of NMDA receptors can further activate metabolism of cholesterol, leading to a vicious cycle of overactivation. All of these mechanisms increase extracellular glutamate and can lead to hyperexcitability. For these reasons, the cholesterol pathway represents a new potential mechanistic target for antiseizure medications. CH24H inhibition has been shown to decrease seizure behavior and improve survival in multiple animal models of epilepsy and could be a promising new mechanism of action for the treatment of neuronal hyperexcitability and developmental and epileptic encephalopathies.

Cholesterol Accelerates Aggregation of α-Synuclein Simultaneously Increasing the Toxicity of Amyloid Fibrils.

A hallmark of Parkinson disease (PD) is a progressive degeneration of neurons in the substantia nigra pars compacta, hypothalamus, and thalamus. Although the exact etiology of irreversible neuronal degeneration is unclear, a growing body of experimental evidence indicates that PD could be triggered by the abrupt aggregation of α-synuclein (α-Syn), a small membrane protein that is responsible for cell vesicle trafficking. Phospholipids uniquely alter the rate of α-Syn aggregation and, consequently, change the cytotoxicity of α-Syn oligomers and fibrils. However, the role of cholesterol in the aggregation of α-Syn remains unclear. In this study, we used Caenorhabditis elegans that overexpressed α-Syn to investigate the effect of low (15%), normal (30%), and high (60%) concentrations of cholesterol on α-Syn aggregation. We found that an increase in the concentration of cholesterol in diets substantially shortened the lifespan of C. elegans. Using biophysical methods, we also investigated the extent to which large unilamellar vesicles (LUVs) with low, normal, and high concentrations of cholesterol altered the rate of α-Syn aggregation. We found that only lipid membranes with a 60% concentration of cholesterol substantially accelerated the rate of protein aggregation. Cell assays revealed that α-Syn fibrils formed in the presence of LUVs with different concentrations of cholesterol exerted very similar levels of cytotoxicity to rat dopaminergic neurons. These results suggest that changes in the concentration of cholesterol in the plasma membrane, which in turn could be caused by nutritional preferences, could accelerate the onset and progression of PD.

SNPs in cytochromes P450 catalyzing cholesterol degradation in brain are associated with Parkinson's disease.

Besides being an essential structural component of plasma membranes and the precursor of many functional compounds and signaling molecules, cholesterol was also proposed to play a role in the etiology and/or manifestation of Parkinson's disease (PD). However, so far systematic investigations on the role of cholesterol and its metabolites present in the brain for the etiology of PD are missing. Here, we investigate for the first time the association of PD with SNPs in the genes of four cytochromes P450 (P450), CYP46A1, CYP39A1, CYP27A1 and CYP7B1, which are critical for the degradation of cholesterol in the brain. Analyzing 1,349 individuals from the PPMI data base, we found 24 SNPs in these four genes, which are significantly over- or under-represented in patients suffering from idiopathic PD (IPD). Studying each of the 362 IPD patients individually, we found that most patients (45%) showed only one associated SNP in one of the four P450 genes, while 31% displayed two associated SNPs and 18% three associated SNPs. The occurrence of some associated SNPs is in the same order of magnitude as SNPs in the GBA (beta-glucocerebrosidase) and thus might reflect a genetic predisposition for PD. As all 24 SNPs were located in introns and 3' untranslated regions, we evaluated the prospective regulatory impact of the surrounding genomic regions by using transcriptome and epigenome data from the Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD). FOUNDIN-PD provides gene expression, open chromatin and DNA methylation data in a cohort of 89 induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons derived from people in the PPMI study. Indeed, two of the 24 SNPs, one in CYP7B1 (rs118111353) and the other one in CYP27A1 (rs74446825), were localized within a region of open chromatin in differentiated neurons. Interestingly, all iPSC lines with open chromatin in rs118111353 showed the reference allele. As all four P450, CYP46A1, CYP39A1, CYP27A1 and CYP7B1, are expressed in dopaminergic neurons, we discuss further functional studies to connect SNPs in regulatory regions with gene expression levels. Finally, potential possibilities for personalized therapeutic treatment of patients with SNPs in the four investigated P450 are discussed.

A high cholesterol diet aggravates experimental colitis through SREBP2-modulated endocytosis and degradation of occludin and Zo-1 proteins.

Disrupted cholesterol homeostasis plays a critical role in the development of multiple diseases, such as cardiovascular disease and cancer. However, the role of cholesterol in inflammatory bowel disease (IBD) remains unclear. In the present study, we investigated whether and how high levels of cholesterol in the diet affect experimental colitis in mice. A normal diet supplemented with 1.25% cholesterol (high cholesterol diet) caused more severe colitis and aggravated the disruption of intestinal tight junction structure, accompanied by higher colonic tissue total cholesterol (TC) levels in a dextran sulfate sodium (DSS)-induced experimental colitis mouse model. Cholesterol aggravated DSS-induced intestinal epithelial barrier impairment and nuclear sterol regulatory element-binding protein 2 (nSREBP2) inhibition both in vivo and in vitro. In addition, nSREBP2 overexpression ameliorated cholesterol-induced intestinal epithelial barrier disruption in Caco2 cells. Interestingly, inhibition of SREBP2 disrupted intestinal epithelial barrier in the absence of cholesterol. Furthermore, SREBP2 regulated the protein expression of tight junction proteins (occludin/Zo-1) via modulating caveolin-1-mediated endocytosis and lysosomal degradation. Analysis of UK Biobank data indicated that, in fully adjusted models, higher serum TC concentrations were an independent protective factor for IBD incidence. The sterol regulatory element-binding factor 2 (SREBF2) gene rs2228313 (G/C) genetic variant was associated with the incidence of IBD and the CC genotype of SREBF2 rs2228313 was associated with higher serum TC levels and decreased the risk of IBD. In summary, a high cholesterol diet aggravates DSS-induced colitis in mice by down-regulating nSREBP2 expression, thereby promoting the endocytic degradation of tight junction proteins. In humans, SREBF2 gene single nucleotide polymorphism rs2228313 and serum TC levels are associated with IBD incidence.

Phenotypic switch of vascular smooth muscle cells in COVID-19: Role of cholesterol, calcium, and phosphate.

Although the novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily manifests as severe respiratory distress, its impact on the cardiovascular system is also notable. Studies reveal that COVID-19 patients often suffer from certain vascular diseases, partly attributed to increased proliferation or altered phenotype of vascular smooth muscle cells (VSMCs). Although the association between COVID-19 and VSMCs is recognized, the precise mechanism underlying SARS-CoV-2's influence on VSMC phenotype remains largely under-reviewed. In this context, while there is a consistent body of literature dissecting the effect of COVID-19 on the cardiovascular system, few reports delve into the potential role of VSMC switching in the pathophysiology associated with COVID-19 and the molecular mechanisms involved therein. This review dissects and critiques the link between COVID-19 and VSMCs, with particular attention to pathways involving cholesterol, calcium, and phosphate. These pathways underpin the interaction between the virus and VSMCs. Such interaction promotes VSMC proliferation, and eventually potentiates vascular calcification as well as worsens prognosis in patients with COVID-19.

The Impact of Cholesterol on Stroke Outcomes: A Cross-Sectional Analysis in Central Java

Introduction: Stroke remains a leading cause of mortality and morbidity globally, with variations in subtypes and risk factors observed across populations. The role of cholesterol in stroke, particularly its association with ischemic and hemorrhagic subtypes, continues to be investigated. This study aimed to examine the relationship between cholesterol levels and stroke outcomes in a Central Javanese population. Methods: A cross-sectional study was conducted at hospitals in Central Java, Indonesia. Data were collected from medical records of patients diagnosed with ischemic or hemorrhagic stroke between January and December 2022. Demographic information, stroke subtype, and cholesterol levels were analyzed. Statistical tests were employed to assess the association between cholesterol and stroke outcomes. Results: The study included 68 patients (34 ischemic, 34 hemorrhagic). The majority of hemorrhagic stroke patients were female (52.9%), while ischemic stroke patients were predominantly male (64.7%). The mean cholesterol level for hemorrhagic stroke patients was 202.59 mg/dL, and for ischemic stroke patients, it was 190.26 mg/dL. Statistical analysis revealed no significant association between cholesterol levels and stroke subtype (p > 0.05). Conclusion: The findings suggest that cholesterol levels may not be a primary determinant of stroke subtype in this Central Javanese population. Further research is warranted to explore other potential risk factors and their interplay with cholesterol in influencing stroke outcomes.

Role of Cholesterol in Interaction of Ionic Liquids with Model Lipid Membranes and Associated Permeability.

In this work, we explored how the amount of cholesterol in the lipid membrane composed of phosphatidylcholine (POPC) or phosphatidylglycerol (POPG) affects the interaction with 1-dodecyl-3-methylimidazolium bromide ([C12MIM]+Br-) ionic liquids using various biophysical techniques. On interacting with the membrane, [C12MIM]+Br- leads to enhanced membrane permeability and induces membrane fusion, leading to an increase in vesicle size. The 2H-based solid-state NMR investigations of cholesterol-containing lipid membranes reveal that [C12MIM]+Br- decreases the lipid chain order parameters and counteracts the lipid condensation effect of cholesterol to some extent. Therefore, as the amount of cholesterol in the membrane increases, the membrane effect of [C12MIM]+Br- decreases. The effect of [C12MIM]+Br- on the membrane properties is more pronounced for POPC compared to that of POPG membranes. This suggests a dependence of these effects on the electrostatic interactions, indicating that the influence of [C12MIM]+Br- varies based on the lipid composition. The findings suggest that the presence of cholesterol can modulate the effect of [C12MIM]+Br- on membrane properties, with variations observed between POPC and POPG membranes, highlighting the importance of lipid composition. In short, this study provides insights into the intricate interplay between cholesterol, the lipid membrane, and the ionic liquid [C12MIM]+Br-.

Evolving Concepts of the SCORE System: Subtracting Cholesterol from Risk Estimation: A Way for a Healthy Longevity?

The role of cholesterol, mainly low-density lipoproteins (LDL-C), as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) is now established and accepted by the international scientific community. Based on this evidence, the European and American guidelines recommend early risk stratification and "rapid" achievement of the suggested target according to the risk estimation to reduce the number of major cardiovascular events. Prolonged exposure over the years to high levels of LDL-C is one of the determining factors in the development and progression of atherosclerotic plaque, on which the action of conventional risk factors (cigarette smoking, excess weight, sedentary lifestyle, arterial hypertension, diabetes mellitus) as well as non-conventional risk factors (gut microbiota, hyperuricemia, inflammation), alone or in combination, favors the destabilization of the atherosclerotic lesion with rupture/fissuration/ulceration and consequent formation of intravascular thrombosis, which leads to the acute clinical manifestations of acute coronary syndromes. In the current clinical practice, there is a growing number of cases that, although extremely common, are emblematic of the concept of long-term exposure to the risk factor (LDL hypercholesterolemia), which, not adequately controlled and in combination with other risk factors, has favored the onset of major cardiovascular events. The triple concept of "go lower, start earlier and keep longer!" should be applied in current clinical practice at any level of prevention. In the present manuscript, we will review the current evidence and documents supporting the causal role of LDL-C in determining ASCVD and whether it is time to remove it from any score.

Cholesterol drives enantiospecific effects of ibuprofen in biomimetic membranes

The interaction between chiral drugs and biomimetic membranes is of interest in biophysical research and biotechnological applications. There is a belief that the membrane composition, particularly the presence of cholesterol, could play a pivotal role in determining enantiospecific effects of pharmaceuticals. Our study explores this topic focusing on the interaction of ibuprofen enantiomers (S- and R-IBP) with cholesterol-containing model membranes. The effects of S- and R-IBP at 20 mol% on bilayer mixtures of dipalmitoylphosphatidylcholine (DPPC) with 0, 10, 20 and 50 mol% cholesterol were investigated using circular dichroism and spin-label electron spin resonance. Morphological changes due to IBP enantiomers were studied with atomic force microscopy on supported cholesterol-containing DPPC monolayers. The results reveal that IBP isoforms significantly and equally interact with pure DPPC lipid assemblies. Cholesterol content, besides modifying the structure and the morphology of the membranes, triggers the drug enantioselectivity at 10 and 20 mol%, with the enantiomers differently adsorbing on membranes and perturbing them. The spectroscopic and the microscopic data indicate that IBP stereospecificity is markedly reduced at equimolar content of Chol mixed with DPPC. This study provides new insights into the role of cholesterol in modulating enantiospecific effects of IBP in lipid membranes.

MiRNA Regulation of Cerebrovascular Inwardly Rectifying K+ Channels During Onset of Alzheimer Disease: Role of Cholesterol and Cannabidiol Treatment

Currently, more than 6 million Americans live with Alzheimer disease (AD). Recent studies demonstrate that impaired blood flow in the brain is integral to the development of AD. Vascular inwardly rectifying K+ channels, such as KIR2.x and KIR6.x, are important for regulating vasoconstriction and vasodilation to tune cerebral perfusion in response to metabolic demand. We’ve previously identified that disruption in membrane cholesterol during advanced AD pathology restores function of KIR2.1 channels to that of young, healthy conditions or better. Additionally, we’ve identified specific microRNAs (miRNAs) in cerebral vessels that can be used to track early development of AD. In this study, we seek to understand molecular pathways stemming from miRNAs that directly or indirectly modulate activity of KIR2.x ( Kcnj2, Kcnj12) and KIR6.x ( Kcnj8, Kcnj11) channels. These ion channels are abundant in cerebrovascular endothelium and smooth muscle cells while particularly sensitive to dyslipidemia. We hypothesize that cerebrovascular miRNAs marking AD pathology are involved in dysregulation of inwardly rectifying K+ channels via cholesterol signaling. With employing QIAGEN’s Ingenuity Pathway Analysis (IPA), we first identified miRNAs that generally regulate each of the target genes for select KIR channels. With applying acquired knowledge of cerebrovascular miRNAs implicated in AD, we found which of these miRNAs also regulate cellular membrane cholesterol levels. Finally, we pinpointed miRNAs sensitive to cannabidiol (CBD) treatment during the development of AD as a potential therapeutic alternative to statins and cyclodextrins. In total, there are 233 miRNAs that regulate Kcnj2, 43 for Kcnj8, 203 for Kcnj11, and 177 for Kcnj12. When factoring in miRNAs that are AD-related, remaining miRNAs include nine that regulate Kcnj2, and one each for Kcnj8, Kcnj11, and Kcnj12. Remaining miRNAs that are cholesterol-related include one for Kcnj2, 43 for Kcnj8, 191 for Kcnj11, and one for Kcnj12. In general, at AD onset, CBD upregulates KIR2.2 and downregulates KIR2.1, KIR6.1, and KIR6.2 channels. CBD reversed expression of miRNAs involved in KIR2.x channel regulation in endothelial and smooth muscle/pericytes (e.g., miR-133 and miR-145) during AD onset in 3xTg-AD animals relative to wild-type controls. CBD also reverses expression of miR-129 and miR-151 to effectively upregulate genes modulating KIR6.x channels from onset of AD relative to wild-type. Altogether, we evidence specific pathways underpinning regulation of KIR2.x and KIR6.x channels in the transition from a healthy to diseased brain. This work was supported by the National Institutes of Health (R01AG073230). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Behavioral and Metabolic Effects of ABCG4 KO in the APPswe,Ind (J9) Mouse Model of Alzheimer’s Disease

The pathogenesis of Alzheimer’s disease (AD) is complex and involves an imbalance between production and clearance of amyloid-ß peptides (Aß), resulting in accumulation of Aß in senile plaques. Hypercholesterolemia is a major risk factor for developing AD, with cholesterol shown to accumulate in senile plaques and increase production of Aß. ABCG4 is a member of the ATP-binding cassette transporters predominantly expressed in the CNS and has been suggested to play a role in cholesterol and Aß efflux from the brain. In this study, we bred Abcg4 knockout (KO) with the APPSwe,Ind (J9) mouse model of AD to test the hypothesis that loss of Abcg4 would exacerbate the AD phenotype. Unexpectedly, no differences were observed in novel object recognition (NOR) and novel object placement (NOP) behavioral tests, or on histologic examinations of brain tissues for senile plaque numbers. Furthermore, clearance of radiolabeled Aß from the brains did not differ between Abcg4 KO and control mice. Metabolic testing by indirect calorimetry, glucose tolerance test (GTT), and insulin tolerance test (ITT) were also mostly similar between groups with only a few mild metabolic differences noted. Overall, these data suggest that the loss of ABCG4 did not exacerbate the AD phenotype.

Lipid Oxidation Products and the Risk of Cardiovascular Diseases: Role of Lipoprotein Transport.

Cholesterol has for decades ruled the history of atherosclerotic cardiovascular diseases (CVDs), and the present view of the etiology of the disease is based on the transport of cholesterol by plasma lipoproteins. The new knowledge of the lipoprotein-specific transport of lipid oxidation products (LOPs) has introduced another direction to the research of CVD, revealing strong associations between lipoprotein transport functions, atherogenic LOP, and CVD. The aim of this review is to present the evidence of the lipoprotein-specific transport of LOP and to evaluate the potential consequences of the proposed role of the LOP transport as a risk factor. The associations of cholesterol and lipoprotein LOP with the known risk factors of CVD are mostly parallel, and because of the common transport and cellular intake mechanisms it is difficult to ascertain the independent effects of either cholesterol or LOP. While cholesterol is known to have important physiological functions, LOPs are merely regarded as metabolic residues and able to initiate and boost atherogenic processes. It is therefore likely that with the increased knowledge of the lipoprotein-specific transport of LOP, the role of cholesterol as a risk factor of CVD will be challenged.

The Relationship Between CYP46A1 Polymorphism and Suicide Risk: A Preliminary Investigation.

Suicide is a global public health issue, with a particularly high incidence in individuals suffering from Major Depressive Disorder (MDD). The role of cholesterol in suicide risk remains controversial, prompting investigations into genetic markers that may be implicated. This study examines the association between CYP46A1 polymorphisms, specifically SNPs rs754203 and rs4900442, and suicide risk in a Mexican MDD patient cohort. Our study involved 188 unrelated suicide death victims, 126 MDD patients, and 144 non-suicidal controls. Genotypic and allelic frequencies were assessed using the Real Time-polymerase chain reaction method, and associations with suicide risk were evaluated using chi-square tests. The study revealed significant differences in allelic and genotypic frequencies in rs754203 SNP between suicide death and controls. The CYP46A1 rs754203 genotype G/G was significantly linked with suicide, and the G allele was associated with a higher risk of suicide (OR = 1.370, 95% CI = 1.002-1.873). However, we did not observe any significant differences in genotype distribution or allele frequencies of CYP46A1 rs4900442. Our study suggests that carriers of the CYP46A1 rs754203 G allele (A/G + G/G) may play a role in suicidal behavior, especially in males. Our findings support that the CYP46A1 gene may be involved in susceptibility to suicide, which has not been investigated previously. These results underscore the importance of further research in different populations to elucidate the genetic underpinnings of the role of CYP46A1 in suicide risk and to develop targeted interventions for at-risk populations.

The role of cholesterol and its oxidation products in tuberculosis pathogenesis.

Mycobacterium tuberculosis causes tuberculosis (TB), one of the world's most deadly infections. Lipids play an important role in M. tuberculosis pathogenesis. M. tuberculosis grows intracellularly within lipid-laden macrophages and extracellularly within the cholesterol-rich caseum of necrotic granulomas and pulmonary cavities. Evolved from soil saprophytes that are able to metabolize cholesterol from organic matter in the environment, M. tuberculosis inherited an extensive and highly conserved machinery to metabolize cholesterol. M. tuberculosis uses this machinery to degrade host cholesterol; the products of cholesterol degradation are incorporated into central carbon metabolism and used to generate cell envelope lipids, which play important roles in virulence. The host also modifies cholesterol by enzymatically oxidizing it to a variety of derivatives, collectively called oxysterols, which modulate cholesterol homeostasis and the immune response. Recently, we found that M. tuberculosis converts host cholesterol to an oxidized metabolite, cholestenone, that accumulates in the lungs of individuals with TB. M. tuberculosis encodes cholesterol-modifying enzymes, including a hydroxysteroid dehydrogenase, a putative cholesterol oxidase, and numerous cytochrome P450 monooxygenases. Here, we review what is known about cholesterol and its oxidation products in the pathogenesis of TB. We consider the possibility that the biological function of cholesterol metabolism by M. tuberculosis extends beyond a nutritional role.

The effects of cholesterol and statins on Parkinson's neuropathology: a narrative review.

Parkinson disease (PD) is chronic and progressive neurodegenerative disease of the brain characterized by motor symptoms including tremors, rigidity, postural instability, and bradykinesia. PD neuropathology is due to the progressive degeneration of dopaminergic neurons in the substantia nigra and accumulation of Lewy bodies in the survival neurons. The brain contains a largest amount of cholesterol which is mainly synthesized from astrocytes and glial cells. Cholesterol is intricate in the pathogenesis of PD and may be beneficial or deleterious. Therefore, there are controversial points concerning the role of cholesterol in PD neuropathology. In addition, cholesterol-lowering agents' statins can affect brain cholesterol. Different studies highlighted that statins, via inhibition of brain HMG-CoA, can affect neuronal integrity through suppression of neuronal cholesterol, which regulates synaptic plasticity and neurotransmitter release. Furthermore, statins affect the development and progression of different neurodegenerative diseases in bidirectional ways that could be beneficial or detrimental. Therefore, the objective of the present review was to clarify the double-sward effects of cholesterol and statins on PD neuropathology.

A novel role of cholesterol in altering the properties of fibrin fibers

A novel role of cholesterol in altering the properties of fibrin fibers

The Role of Cholesterol during the Ovarian Maturation and Lipid Metabolism of Female Chinese Mitten Crab (Eriocheir sinensis)

In previous study, we found that the cholesterol requirement of Eriocheir sinensis was 0.27%, to further investigate the effects of cholesterol on health status, ovarian maturation, and lipid metabolism of female Eriocheir sinensis broodstock. Two diets containing 0% and 0.25% (actually 0.05% and 0.27%) cholesterol were fed to the female crabs (average weight: 49.21 ± 0.11 g) for 4 months and sampled once a month. The results showed that the body weight (BW), survival rate (SR), meat yield (MY), condition factor (CF), hepatosomatic index (HSI), and gonadosomatic index (GSI) of Eriocheir sinensis were significantly affected by treatment time and compared with the cholesterol deficient group, supplementing cholesterol significantly increased BW, HSI, and GSI (P<0.05). In addition, long-term lack of cholesterol will lead to a significant decrease in the activity of ACP, AKP, and SOD and a significant increase in the content of MDA. The histological results showed that cholesterol significantly increased the volume of oocytes (P<0.05). Further studies found that 0.27% cholesterol significantly increased the transcription levels of vtg and vgr in hepatopancreas and ovaries, which may be the main reason for the increase of oocyte size (P<0.05). When fed with 0.27% cholesterol diet, the contents of nutrients in hepatopancreas and ovaries increased significantly, especially lipids and cholesterol (P<0.05). Through the analysis of mRNA expression level of genes related to lipid metabolism, it was found that cholesterol enhanced the transcription level of genes related to lipid synthesis and transport in hepatopancreas, thereby promoting the accumulation of lipid in the organism. Furthermore, compared with control group, the levels of juvenile hormone (JH), 17β-estradiol (E2), methyl farnesoate (MF), and ecdysone in the organism were significantly increased after feeding a diet with 0.27% cholesterol (P<0.05). In summary, supplementing an appropriate amount of cholesterol in the diet can improve the growth performance of Eriocheir sinensis broodstock, enhance the body’s antioxidant and immune system, and promote the accumulation of nutrients in the ovaries, thereby promoting ovarian maturation.

Changes in bile acid composition are correlated with reduced intestinal cholesterol uptake in intestine-specific WASH-deficient mice

The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is a pentameric protein complex localized at endosomes, where it facilitates the transport of numerous receptors from endosomes toward the plasma membrane. Recent studies have shown that the WASH complex plays an essential role in cholesterol and glucose homeostasis in humans and mice. To investigate the physiological importance of intestinal WASH, we ablated the WASH component WASHC1 specifically in murine enterocytes. Male and female intestine-specific WASHC1-deficient mice (Washc1IKO) were challenged with either a standard chow diet or a high-cholesterol (1.25 %) diet (HCD). Washc1IKO mice fed a standard diet did not present any apparent phenotype, but when fed an HCD, their hepatic cholesterol levels were ~ 50 % lower compared to those observed in control mice. The intestinal cholesterol absorption was almost 2-fold decreased in Washc1IKO mice, which translated into increased fecal neutral sterol loss. The intestinal expression of cholesterogenic genes, such as Hmgcs1, Hmgcr, and Ldlr, was significantly higher in Washc1IKO mice than in control mice and correlated with increased whole-body de novo cholesterol synthesis, likely to compensate for impaired intestinal cholesterol absorption. Unexpectedly, the ratio of biliary 12α−/non-12α-hydroxylated bile acids (BAs) was decreased in Washc1IKO mice and reversing this reduced ratio by feeding the mice with the HCD supplemented with 0.5 % (w/w) sodium cholate normalized the improvement of hepatic cholesterol levels in Washc1IKO mice. Our data indicate that the intestinal WASH complex plays an important role in intestinal cholesterol absorption, likely by modulating biliary BA composition.