Disorder Of Cholesterol Metabolism Research Articles

Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin-mediated endocytosis.

SUMMARYClathrin-mediated endocytosis (CME) is critical for cellular signal transduction, receptor recycling, and membrane homeostasis in mammalian cells. Acute depletion of cholesterol disrupts CME, motivating analysis of CME dynamics in the context of human disorders of cholesterol metabolism. We report that inhibition of post-squalene cholesterol biosynthesis impairs CME. Imaging of membrane bending dynamics and the CME pit ultrastructure reveals prolonged clathrin pit lifetimes and shallow clathrin-coated structures, suggesting progressive impairment of curvature generation correlates with diminishing sterol abundance. Sterol structural requirements for efficient CME include 3′ polar head group and B-ring conformation, resembling the sterol structural prerequisites for tight lipid packing and polarity. Furthermore, Smith-Lemli-Opitz fibroblasts with low cholesterol abundance exhibit deficits in CME-mediated transferrin internalization. We conclude that sterols lower the energetic costs of membrane bending during pit formation and vesicular scission during CME and suggest that reduced CME activity may contribute to cellular phenotypes observed within disorders of cholesterol metabolism.

Integrating Patient-Reported Outcomes Into Clinical Genetic Testing for Familial Hypercholesterolemia.

Patient-reported outcomes (PROs) and PRO measures (PROMs) are often used to help clinicians and researchers understand patients' personal concerns, feelings, experiences, and perspectives following the implementation of an intervention. Notably, PROs and PROMs can inform health systems, health policy, and payers on the utility of clinical genetic testing based on each patient's personal values, perspectives, and potential health behaviors subsequent to testing. In this topic synopsis, we discuss the underexplored role of and implications for PROs and PROMs following genetic testing for familial hypercholesterolemia (FH), an autosomal dominant genetic disorder of cholesterol metabolism that can lead to highly premature fatal and nonfatal myocardial infarction and stroke. We also discuss why the use and consideration of patient perspectives, via PROs and PROMs, are critical to the process of optimizing patient care across various FH treatment contexts. As expert clinician groups consider the latest evidence when establishing recommendations for FH genetic testing, there is a ripe opportunity for clinicians and researchers to explore the value and utility of PROs to inform and possibly improve care for patients diagnosed with FH.

Deficiency of coiled-coil domain containing 80 increases plasma cholesterol by decreasing fecal sterols excretion in hypercholesterolemic mice

Disorders in cholesterol and bile acid metabolism have been acknowledged as critical in pathogenesis of hypercholesterolemia. Coiled-coil domain containing 80 (CCDC80) has been closely linked to lipid homeostasis in mice, with its role in cholesterol metabolism yet to be fully elucidated. This study aims to uncover the regulatory mechanisms of CCDC80 in diet-induced hypercholesterolemia. We generated a CCDC80 knockout (CCDC80−/−) model in C57BL/6 mouse. The initial transcriptional and metabolic consequences of removing CCDC80 were accessed at baseline by gene expression microarrays and gas chromatography-mass spectrometry / ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, respectively. The hepatic cholesterol was investigated in both CCDC80+/+ and CCDC80−/− male mice at baseline and after feeding a high-cholesterol diet for 12 weeks. The regulatory effects of CCDC80 on gene expressions and protein masses were measured by RT-qPCR and western blot, respectively. At baseline, the KEGG pathway enrichment analysis combining metabolomics, lipidomics and transcriptomics, revealed a down-regulation of hepatic bile acid biosynthesis by CCDC80-knockout, especially for primary bile acids. In the hypercholesterolemic models, our results showed that deficiency of CCDC80 increased plasma and liver cholesterol levels, but decreased fecal neutral and acidic sterols excretion in mice. Mechanistically, we found that such effects were partly mediated by attenuating the alternative pathway of bile acid synthesis catalyzed by oxysterol 7-alpha-hydroxylase (CYP7B1). In conclusion, our results suggest CCDC80 as a novel modulator of cholesterol homeostasis in male mice. Deficiency of CCDC80 could further impair fecal sterols excretion in diet-induced hypercholesterolemia.

Effects of sublethal concentration of metamifop on hepatic lipid metabolism in adult zebrafish (Danio rerio).

Metamifop (MET) is an effective herbicide that has been extensively used in paddy fields. Previous research demonstrated that MET was highly toxic to zebrafish embryos, and this threat has caused great concern; moreover, 0.40 mg/L MET elevated the hepatosomatic index (HSI) in adult zebrafish without lethal effect after 21 d of exposure. In this study, we further determined the detailed impacts of MET on adult zebrafish at sublethal concentrations (0.025, 0.10 and 0.40 mg/L). We found that 0.40 mg/L MET caused liver injury by increasing the activity of aspartate aminotransferase and alanine aminotransferase in plasma, the content of interleukin-1β, IL-6, tumor necrosis factor-α, and mRNA expression level of genes associated with inflammatory response in liver of adult zebrafish. The hepatic triglyceride (TG), free fatty acid and fatty acid synthase levels were significantly elevated in 0.40 mg/L MET-treated group (1.55-, 2.20- and 2.30-fold, respectively), and the transcript of lipid accumulation-related genes (fabp10, fas, acc, chrebp, dagt2 and agpat4) were upregulated. Meanwhile, the total cholesterol content was decreased by 0.48-fold, bile acid level was increased by 2.44-fold, and levels of cholesterol metabolism-related genes (apoa-1a, hmgcra, cyp51, dhcr7 and cyp7a1) were increased, suggesting cholesterol metabolism disorder occurred in zebrafish. Furthermore, analysis of lipidomics revealed that 0.40 mg/L MET significantly increased the abundance of 91 lipids, which mainly belonged to TG lipid class and were enriched in pathways of glycerolipid metabolism, cholesterol metabolism, etc. These results suggested that MET exposure at sublethal concentrations would induce hepatic inflammation and lipid metabolism disorders in adult zebrafish.

Pathophysiology of Cardiovascular Diseases and the Role of Vitamins, and Herbal Extracts in the Reduction of Cardiovascular Risks

Heart disease (cardiovascular disease: CVD) is considered the leading cause of worldwide death. These diseases are recognized as group of disorders which are related to heart and blood vessels. Generally, heart diseases are considered life style associated diseases but many other factors are also found associated with cardiovascular diseases. The aim of this review is to provide the till date information regarding local and circulatory disorders, role of different vitamins and herbs on heart diseases. This review article contains a detailed survey of literature about cardiovascular diseases, which was available in different online databases such as; PubMed, Web of Science, Science Direct, Elsevier, and Google Scholar, etc. In this review, the authors have focused on the description of cardiovascular disorders, their pathophysiological properties and importance of micronutrients, vitamins and herbs in the management of cardiovascular diseases. Cardiovascular diseases are considered responsible for approximately 17.9 million deaths annually at the global level. Surprisingly, low- and middle-income countries count for 75% of CVD deaths. These diseases represent disorders related to circulatory systems specially heart and coronary arteries. Many lifestyle associated factors such as; high cholesterol consumption, smoking, alcohol consumption, tobacco use, metabolic disorders, stress, and other factors such as; family history, age, gender and genetic factors, etc. have been found involved in occurrence of CVDs. That's why management of diet, management of tobacco and alcohol consumption, management of stress, increased physical activities are considered population-wide strategies for control cardiovascular diseases. On the basis of pathophysiology, heart diseases are of many types and out of them, Acute Myocardial Infarction (AMI) and Sudden Cardiac Death (SCD) are considered serious and catastrophic cardiac disorders. Intake of vitamins, micronutrients, lycopene, omega 3 fatty acid and many herbs like Crataegus oxyacantha (Hawthron), Allium sativum (garlic), Salvia miltiorrhiza (Danshen), Ganoderma lucidum (lingzhi), Ginkgo biloba have been identified good for cardiovascular diseases management and treatment. Cardiovascular diseases are considered one of the fatal clinical conditions, as many of them are asymptomatic. The regulation of diet, increased physical activities, and healthy lifestyle are recommended to control the development of cardiovascular problems. Including this, scientific studies have supported the role of many vitamins, nutrients and herbs as beneficial in cardiovascular diseases, but many of them could not demonstrate their role at clinical level but it is suggested that their role as nutrients can not be ignored and their consumption may reduce the cardiovascular risks.

Hepatic lysosomal acid lipase drives the autophagy-lysosomal response and alleviates cholesterol metabolic disorder in ApoE deficient mice

Lysosomal acid lipase (LAL)-dependent lipolysis degrades cholesteryl ester (CE) and triglyceride in the lysosome. LAL deficiency in human and mice leads to hypercholesterolemia, hepatic CE deposition, and atherosclerosis. Despite its hepatocyte-specific deficiency leads to CE accumulation, the regulation of LAL in cholesterol metabolic disease remains elusive. For the in vitro study, the target gene Lipa was transfected with recombinant shRNA or lentiviral vector in Hepa1-6 cells. It was found that LAL silencing in cells affected lysosomal function by reducing LAL activity and proteolytic activity, and altered the expression of genes related to cholesterol metabolism and autophagy, leading to cholesterol accumulation; whereas LAL overexpression improved the above effects. To explore the impacts of hepatic LAL on cholesterol metabolic disease in vivo, apolipoprotein E deficient (ApoE−/−) mice were intravenously injected with lentivirus to achieve hepatic LAL overexpression and fed a Western diet for 16 weeks. The results showed that hepatic LAL overexpression significantly reduced plasma lipid levels, alleviated inflammation and oxidative status in plasma and liver, and attenuated hepatic steatosis and fibrosis in ApoE−/− mice. Mechanically, hepatic LAL promoted cholesterol transport and biliary excretion by increasing liver X receptor alpha (LXRα) and its downstream genes, and modulated the compliance of the autophagy-lysosomal pathway. Our data provide the original evidence of the validity of hepatic LAL in controlling cholesterol metabolism and liver homeostasis, suggesting that targeting hepatic LAL may provide a promising approach to rescue cholesterol metabolic disorders, such as hypercholesterolemia and liver disease.

LXR-Mediated Regulation of Marine-Derived Piericidins Aggravates High-Cholesterol Diet-Induced Cholesterol Metabolism Disorder in Mice.

Reported as two antirenal cell carcinoma (RCC) drug candidates, marine-derived compounds piericidin A (PA) and glucopiericidin A (GPA) exhibit hepatotoxicity in renal carcinoma xenograft mice. Proteomics and transcriptomics reveal the hepatotoxicity related with cholesterol disposition since RCC is characterized by cholesterol accumulation. PA/GPA aggravate hepatotoxicity in high-cholesterol diet (HCD)-fed mice while exhibiting no toxicity in chow diet-fed mice. High cholesterol accumulation in liver is liver X receptor (LXR)-mediated cytochrome P450 family 7 subfamily a member 1 (CYP7A1) depression and low-density lipoprotein receptor (LDLR) activation. The farnesoid X nuclear receptor (FXR) is also depressed with a downregulated target gene OSTα. Different from PA directly combined with LXRα as an inhibitor, GPA exists as a prodrug in the liver and exerts toxic effects due to transformation into PA. Surface plasmon resonance (SPR) and docking results of 17 piericidins illustrate that glycosides exert no LXRα binding activity. A longer survival time of GPA-treated mice indicates that further exploration in anti-RCC drug research should focus on reducing glycosides transformed into PA and concentrating in the kidney tumor rather than the liver for lowering the risk of hepatotoxicity.

Long-Term Disturbed Expression and DNA Methylation of SCAP/SREBP Signaling in the Mouse Lung From Assisted Reproductive Technologies.

Assisted reproductive technology (ART) has been linked to cholesterol metabolic and respiratory disorders later in life, but the mechanisms by which biosynthetic signaling remain unclear. Lung inflammatory diseases are tightly linked with the sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP), but this has not been shown in an ART offspring. Here, mouse models from a young to old age were established including in vitro fertilization (IVF), intracytoplasmic injection (ICSI), and in vivo fertilized groups. In our results, significantly higher plasma levels of CRP, IgM, and IgG were identified in the aged ICSI mice. Additionally, pulmonary inflammation was found in four aged ART mice. At three weeks, ART mice showed significantly downregulated levels of Scap, Srebp-1a, Srebp-1c, and Srebf2 mRNA in the lung. At the same time, significant differences in the DNA methylation rates of Scap-Srebfs and protein expression of nuclear forms of SREBPs (nSREBPs) were detected in the ART groups. Only abnormalities in the expression levels of Srebp-1a and Srebp-1c mRNA and nSREBP1 protein were found in the ART groups at 10 weeks. However, at 1.5 years old, aberrant expression levels and DNA methylation of SCAP, SREBP1, and SREBP2, and their associated target genes, were observed in the lung of the ART groups. Our results indicate that ART increases long-term alterations in SCAP/SREBP expression that may be associated with their aberrant methylation status in mouse.

Proteomic Analysis Identifies Prolonged Disturbances in Pathways Related to Cholesterol Metabolism and Myocardium Function in the COVID-19 Recovery Stage.

The COVID-19 pandemic has become a worldwide health crisis. So far, most studies have focused on the epidemiology and pathogenesis of this infectious disease. Little attention has been given to the disease sequelae in patients recovering from COVID-19, and nothing is known about the mechanisms underlying these sequelae. Herein, we profiled the serum proteome of a cohort of COVID-19 patients in the disease onset and recovery stages. Based on the close integration of our proteomic analysis with clinical data, we propose that COVID-19 is associated with prolonged disorders in cholesterol metabolism and myocardium, even in the recovery stage. We identify potential biomarkers for these disorders. Moreover, severely affected patients presented more serious disturbances in these pathways. Our findings potentially support clinical decision-making to improve the prognosis and treatment of patients.

Pravastatin ameliorated osteoarthritis susceptibility in male offspring rats induced by prenatal ethanol exposure.

Osteoarthritis (OA) is a disease associated with a disorder of cholesterol metabolism. Our previous studies showed that prenatal ethanol exposure (PEE) caused cholesterol accumulation in articular cartilage and increased the susceptibility to OA in offspring. However, we did not determine whether pravastatin, a cholesterol-lowering agent, could rescue PEE-induced susceptibility to OA. Here, fetal rats were divided into a PEE group and a control group during pregnancy. At postnatal week (PW) 8, sixteen male offspring rats from both groups were injected papain through the articular cavity. Eight of them from each group were treated with pravastatin (20mg/kg·d) by gavage for four weeks simultaneously. We found that pravastatin ameliorated papain-induced high expression of inflammatory factors [interleukin (IL)-1, IL-6], matrix degradation enzymes [matrix metalloproteinase (MMP)-3, MMP-13], and apoptosis factors (caspase-3 and caspase-8) in the cartilage of the PEE group. Also, pravastatin significantly reduced the content of TCH in the blood and cartilage of the PEE offspring and improved cholesterol efflux pathway. Our in vitro findings further confirmed that pravastatin partially reversed cholesterol-induced inflammation and apoptosis of chondrocytes. In conclusion, pravastatin effectively reduced inflammation and matrix degradation, and thus ameliorate OA susceptibility in articular cartilage by relieving cholesterol accumulation in chondrocyte.

Sterols Lower Energetic Barriers of Membrane Bending and Fission Necessary for Efficient Clathrin Mediated Endocytosis

As the principal internalization mechanism in mammalian cells, clathrin-mediated endocytosis (CME) is critical for cellular signal transduction, receptor recycling, and membrane homeostasis. Acute depletion of cholesterol disrupts CME, motivating analysis of CME dynamics in the context of disrupted cholesterol synthesis, sterol specificity, mechanisms involved, and relevance to disease pathology. Using genome-edited cell lines, we demonstrate that inhibition of post-squalene cholesterol biosynthesis as observed in inborn errors of cholesterol metabolism, results in striking immobilization of CME and impaired transferrin uptake. Imaging of membrane bending dynamics and CME pit ultrastructure revealed prolonged clathrin pit lifetimes and accumulation of shallow clathrin-coated structures that scaled with diminishing sterol abundance. Moreover, fibroblasts derived from Smith-Lemli-Opitz syndrome subjects displayed reduced CME function. We conclude that sterols lower the energetic costs of membrane bending during pit formation and vesicular scission during CME and suggest reduced CME contributes to cellular phenotypes observed within disorders of cholesterol metabolism.

Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets

Cholesterol is an indispensable component of the cell membrane and plays vital roles in critical physiological processes. Brain cholesterol accounts for a large portion of total cholesterol in the human body, and its content must be tightly regulated to ensure normal brain function. Disorders of cholesterol metabolism in the brain are linked to neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other atypical cognitive deficits that arise at old age. However, the specific role of cholesterol metabolism disorder in the pathogenesis of neurodegenerative diseases has not been fully elucidated. Statins that are a class of lipid-lowering drugs have been reported to have a positive effect on neurodegenerative diseases. Herein, we reviewed the physiological and pathological conditions of cholesterol metabolism and discussed the possible mechanisms of cholesterol metabolism and statin therapy in neurodegenerative diseases.

RNA-binding protein hnRNPR reduces neuronal cholesterol levels by binding to and suppressing HMGCR.

Recent studies have identified multiple RNA-binding proteins tightly associated with lipid and neuronal cholesterol metabolism and cardiovascular disorders. However, the role of heterogeneous nuclear ribonucleoprotein R (hnRNPR) in cholesterol metabolism and homeostasis, whether it has a role in regulating 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), is largely unknown. This research identifies hnRNPR as a repressor of HMGCR. Knockdown and overexpression of hnRNPR in cultured neuroblastoma cell (N2a) and MN1 cell lines enhances and inhibits HMGCR in vitro, respectively. hnRNPR may exert its repressive activity on HMGCR mRNA and protein levels by using its RNA recognition motif (RRM) in recognizing and modulating the stability of HMGCR transcript. Our RNA immunoprecipitation and luciferase reporter assays demonstrate a direct interaction between hnRNPR and HMGCR mRNA. We also demonstrated that hnRNR binds to the 3' untranslated region (3' UTR) of HMGCR and reduces its translation, while hnRNPR silencing increases HMGCR expression and cholesterol levels in MN1 and N2a cells. Overexpression of HMGCR significantly restores the decreased cholesterol levels in hnRNPR administered cells. Taken together, we identify hnRNPR as a novel post-transcriptional regulator of HMGCR expression in neuronal cholesterol homeostasis.

Prevalence of Cardiovascular Risk Factors and Heterozygous Familial Hypercholesterolemia in Premature Atherosclerotic Patients Presenting with Acute Coronary Syndrome

Background: Heterozygous familial hypercholesterolemia is an autosomal dominant genetic disorder with an estimated prevalence of 1/200 - 1/500 in the general population. Early identification of patient with familial hypercholesterolemia is important, because appropriate treatment may reduce the risk of premature atherosclerosis. Objective: Assessment of the prevalence of different modifiable cardiovascular risk factors and clinical diagnosis of heterozygous familial hypercholesterolemia. Methods: One hundred patients were enrolled, included young patients (males less than 50 years and females less than 60 years old) presented with first attack of acute coronary syndrome either ST elevation myocardial infarction (STEMI), non ST elevation myocardial infarction (NSTEMI) or unstable angina (UA). All patients were subjected to full history taking, general and local examination, Electrocardiogram, transthoracic Echocardiography, laboratory investigations, coronary angiography and Dutch score calculation for familial hyperlipidemias. Results: The mean level of serum cholesterol among studied group was 268.31 ± 59.33, HDL-C was 39.63 ± 7.52, LDL was 192.27 ± 60.61 and TG was 180.10 ± 39.64. With application of Dutch score, 20% of patients diagnosed definite familial hypercholesterolemia with Dutch score > 8. Twenty-six percent of patients diagnosed as probable familial hypercholesterolemia with Dutch score 6 - 8. Thirty-nine percent patients diagnosed as possible familial hypercholesterolemia with Dutch score 3 - 5 and 15% of patients were unlikely familial hypercholesterolemia with Dutch score 3 with significant correlation between Dutch score and age, total cholesterol, LDL-C, serum creatinine. Conclusion: Familial hypercholesterolemia (FH) is one of the most common serious genetic disorders of cholesterol metabolism. The early identification of heterogynous FH patients is crucial to start an effective prevention strategy.

The interaction between group 2 innate lymphoid cells and lipid metabolism

Abstract Innate lymphoid cells (ILCs) have been found in many tissue sites but are enriched in barrier surfaces such as intestine, lung and skin. They lack antigen-specific receptors yet respond to alarmin signals that are released by tissue, to resemble the cytokine production and effector function of T cells. ILCs play important roles in host defense, tissue repair, autoimmune disorders, inflammation, metabolic homeostasis and more. Recent progress in immunometabolism has highlighted the diverse roles of lipid metabolism in the response and function of immune cells including lymphocytes. But the interaction between ILC2s and lipid metabolism is poorly understood. Our preliminary studies show that, upon activation, intestinal ILC2s significantly upregulate the expression of several genes that are important for cholesterol metabolism. Cholesterol is an essential structural component of mammalian cell membranes and is the precursor for bile acids, vitamin D and steroid hormones. Cholesterol metabolism disorder leads to severe diseases such as hypercholesterolemia, atherosclerosis and diabetes. By using various mouse models and multi-disciplinary experimental approaches, we will study if and how cholesterol regulates the homeostasis, activation and cytokine production of ILC2s and if cholesterol regulation on ILC2s contributes to host defense against helminth infection. We will also investigate if ILC2s in turn modulate lipid, especially cholesterol, metabolism and if ILC2s play any role in hypercholesterolemia or atherosclerosis.

Prospects for the use of chondroitin sulfate and glucosamine sulfate with osteoarthritis associated with pathology of the kidneys and urinary system

Introduction. Chondroitin sulfate (CS) and glucosamine sulfate (GS), widely used as chondroprotectors, can maintain the normal functioning of the urinary system but their effect has not been analyzed systematically.Aim: to perform a systematic analysis of the possibilities of using CS and GS in patients with pathology of the kidneys and urinary system.Materials and methods. Predictive analysis of 2,093 publications on the interactions of CS/GS with the functioning of the kidneys and other organs of the urinary system found at the request “(urinary OR bladder OR kidney) AND (glucosamine OR chondroitin)” by methods of the theory of topological data analysis.Results. Disorders of cholesterol and glucosamine metabolism are characteristic of cystitis, glomerular nephritis, urinary tract infections (UTIs), urolithiasis, proteinuria, and formation of diabetic nephropathy. In addition to inhibiting the pro-inflammatory cascade NF-kB, CS/GS contribute to eliminating the deficiency of glycosaminoglycans in the pathology of urothelium, inhibit urolithiasis, inhibit the synthesis of pro-inflammatory nitric oxide NO in macrophages, and modulate O-glycosylation processes.Conclusion. The results of fundamental and clinical studies show that subsidies of CS/GS substances of pharmacological quality per os and CS instillation in the bladder (in particular, in combination with hyaluronic acid) are the means of choice for patients suffering from osteoarthritis and diseases of the urinary system. Highly purified pharmacological CS substances are part of the preparation Chondroguard.

Role of Baicalin and Liver X Receptor Alpha in the Formation of Cholesterol Gallstones in Mice.

This study was aimed at investigating the effect of baicalin on experimental cholesterol gallstones in mice. The mouse gallstone model was induced by feeding with a lithogenic diet, and cholesterol stones were found in the gallbladder. The lithogenic diet caused elevation of triglycerides, cholesterol, and low-density lipoprotein concentrations and descent of high-density lipoprotein concentration in serum. Hyperplasia and inflammatory infiltration were observed in the gallbladder wall of lithogenic diet-fed mice. We also found the increase of cholesterol content and the decrease of bile acid in bile. Real-time PCR and western blot results demonstrated that the expression levels of two enzymes (cholesterol 7α-hydroxylase (CYP7a1) and sterol 12α-hydroxylase (CYP8b1)) to catalyze the synthesis of bile acid from cholesterol were decreased and that two cholesterol transporters (ATP-binding cassette transporter G5/G8 (ABCG5/8)) were increased in the liver of lithogenic diet-fed mice. The lithogenic diet also led to enhanced activity of alanine aminotransferase and aspartate aminotransferase in serum; increased concentrations of tumor necrosis factor-α, interleukin- (IL-) 1β, IL-6, and malondialdehyde; and decreased superoxide dismutase activity in the liver, suggesting inflammatory and oxidative stress. In addition, liver X receptor alpha (LXRα) was increased in the liver. After gavage of baicalin, the lithogenic diet-induced gallstones, hyperlipidemia, gallbladder hyperplasia, inflammation, and oxidative stress in liver and cholesterol metabolism disorders were all alleviated to some degree. The expression of LXRα in the liver was inhibited by baicalin. In addition, the LXRα agonist T0901317 aggravated lithogenic diet-induced harmful symptoms in mice, including the increase of gallstone formation, hyperlipidemia, hepatic injury, inflammation, and oxidative stress. In conclusion, we demonstrated that baicalin played a protective role in a lithogenic diet-induced gallstone mouse model, which may be mediated by inhibition of LXRα activity. These findings may provide novel insights for prevention and therapy of gallstones in the clinic.

A Global Review on the Utility of Genetic Testing for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disorder of cholesterol metabolism that affects an estimated 1/250 persons in the United States and abroad. FH is hallmarked by high low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. This review summarizes recent global evidence showing the utility of FH genetic testing across diverse populations. Clinical and other qualitative outcomes following FH genetic testing were improved FH diagnosis, treatment initiation or continued treatment, treatment modification, improved total or LDL cholesterol levels, education on lifestyle management, and genetic counseling. This summary of evidence should be considered by those seeking overall evidence and knowledge gaps on the utility of FH genetic testing from a global perspective and for certain ethnic and age populations. These findings can be used to inform insurance policies and coverage decisions for FH genetic testing, policy recommendations to reduce the clinical and public health burden of FH, clinical practice and guidelines to improve the management of FH populations, and ongoing research involving FH genetic testing. We conclude that further investigations are needed to examine: (1) non-clinical outcomes following FH genetic testing; (2) patient-reported outcomes following FH genetic testing to convey patient experiences, values, and goals; and (3) clinical outcomes following FH genetic testing in non-Caucasian and pediatric populations in the United States and abroad.

Differential effects of Chinese high-fat dietary habits on lipid metabolism: mechanisms and health implications

BackgroundThe traditional Chinese diet blends lard with vegetable oil, keeping the fatty acid balance intake ratio of saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids at nearly 1:1:1. However, the effects of a mixture of lard and vegetable oil on lipid metabolism have never been researched. In the present study, by simulating Chinese high-fat dietary habits, we explored the effects of a mixture of lard and vegetable oil on lipid metabolism.MethodsWe randomly assigned 50 male C57BL/6 J mice to 5 groups (10 in each group) and fed them lard, sunflower oil (SFO), soybean oil (SBO), lard blended with sunflower oil (L-SFO), or lard blended with soybean oil (L-SBO) for 12 weeks.ResultsWe found that the final body weights of mice in the lard group were significantly higher than those of mice in the SFO and SBO groups. Body fat rate and volume of fat cell of the lard group were significantly higher than those of the SFO, SBO, and L-SBO groups. Liver triglyceride level of the lard group increased significantly compared to the other groups. Although body fat rate and liver triglyceride level in the SBO and SFO groups decreased compared to those in the other groups, the high-density lipoprotein cholesterol/low-density lipoprotein cholesterol ratio were also significantly decreased in the SBO and SFO groups.ConclusionsWe found that a lard diet induced accumulation of body fat, liver and serum lipids, which can increase the risk of obesity, non-alcoholic fatty acid liver disease, and atherosclerosis. The vegetable oil diet resulted in cholesterol metabolism disorders even though it did not lead to obesity. The mixed oil diet induced body fat accumulation, but did not cause lipid accumulation in the liver and serum. Thus, differential oil/fat diets have an impact on differential aspects in mouse lipid metabolism.Graphical abstract

Screening ToxCast™ for Chemicals That Affect Cholesterol Biosynthesis: Studies in Cell Culture and Human Induced Pluripotent Stem Cell–Derived Neuroprogenitors

Background:Changes in cholesterol metabolism are common hallmarks of neurodevelopmental pathologies. A diverse array of genetic disorders of cholesterol metabolism support this claim as do multiple lines of research that demonstrate chemical inhibition of cholesterol biosynthesis compromises neurodevelopment. Recent work has revealed that a number of commonly used pharmaceuticals induce changes in cholesterol metabolism that are similar to changes induced by genetic disorders with devastating neurodevelopmental deficiencies.Objectives:We tested the hypothesis that common environmental toxicants may also impair cholesterol metabolism and thereby possibly contribute to neurodevelopmental toxicity.Methods:Using high-throughput screening with a targeted lipidomic analysis and the mouse neuroblastoma cell line, Neuro-2a, the ToxCast™ chemical library was screened for compounds that impact sterol metabolism. Validation of chemical effects was conducted by assessing cholesterol biosynthesis in human induced pluripotent stem cell (hiPSC)–derived neuroprogenitors using an isotopically labeled cholesterol precursor and by monitoring product formation with UPLC-MS/MS.Results:Twenty-nine compounds were identified as validated lead-hits, and four were prioritized for further study (endosulfan sulfate, tributyltin chloride, fenpropimorph, and spiroxamine). All four compounds were validated to cause hypocholesterolemia in Neuro-2a cells. The morpholine-like fungicides, fenpropimorph and spiroxamine, mirrored their Neuro-2a activity in four immortalized human cell lines and in a human neuroprogenitor model derived from hiPSCs, but endosulfan sulfate and tributyltin chloride did not.Conclusions:These data reveal the existence of environmental compounds that interrupt cholesterol biosynthesis and that methodologically hiPSC neuroprogenitor cells provide a particularly sensitive system to monitor the effect of small molecules on de novo cholesterol formation. https://doi.org/10.1289/EHP5053