Disorder Of Cholesterol Metabolism Research Articles

Crosstalk between skeletal muscle ratio and cholesterol metabolism disorders: a cross-section study

BackgroundDysfunction of cholesterol metabolism may be associated with low skeletal muscle mass. This study aimed to explore the relationship between skeletal muscle mass and cholesterol metabolic disorders in adults.MethodsThe data of a total of 5949 people with complete medical history data, biochemical data and body composition analysis were recruited. According to the serum cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and nonHDL, the population was divided into a disorder group and a normal group. Independent sample t tests, chi-square tests, Pearson's correlation analyses and binary logistic regression analyses were used to study the effect of body composition on abnormal cholesterol metabolism. According to BMI and sex, the population was divided into different subgroups, and binary logistic regression analysis was used to study the effect of the skeletal mass ratio on cholesteral metabolic disorders in different subgroups.ResultsThere were significant differences in sex, alcohol consumption, body weight, BMI, skeletal muscle mass index (SMI) [total skeletal muscle mass (kg)/height 2 (m2)] and skeletal muscle mass ratio (SMR) [total skeletal muscle mass (kg)/weight (kg) *100] between the disorder group (hypercholesterolemia, hyper-LDL, lower-HDL and hyper-nonHDL) and the normal group. Pearson correlation analysis revealed that the SMR was negatively correlated, while the SMI was positively correlated with cholesterol metabolic disorders in both sexes. The overweight group was older and had a greater SMI, abnormal cholesteral metabolism ratio and lower SMR than the normal-weight group. In the normal-weight group, the SMR was an independent protective factor against different kinds of cholesteral metabolic disorders in both sexes, while the SMI was a risk factor. In the overweight subgroup, the protective effect on HDL and nonHDL metabolism remained in the male subgroup but disappeared in the female subgroup. However, the SMI was an independent risk factor for different kinds of cholesteral metabolic disorders in both sexes.ConclusionsSMR was an independent protective factor against cholesterol metabolic disorders in both males and females, especially in the normal weight group. SMI was an independent risk factor, especially in the overweight group.

The Regulation of Frontal Cortex Cholesterol Metabolism Abnormalities by NR3C1/NRIP1/NR1H2 Is Involved in the Occurrence of Stress-Induced Depression

Stress-induced alterations in central neuron metabolism and function are crucial contributors to depression onset. However, the metabolic dysfunctions of the neurons associated with depression and specific molecular mechanisms remain unclear. This study initially analyzed the relationship between cholesterol and depression using the NHANES database. We then induced depressive-like behaviors in mice via restraint stress. Applying bioinformatics, pathology, and molecular biology, we observed the pathological characteristics of brain cholesterol homeostasis and investigated the regulatory mechanisms of brain cholesterol metabolism disorders. Through the NHANES database, we initially confirmed a significant correlation between cholesterol metabolism abnormalities and depression. Furthermore, based on successful stress mouse model establishment, we discovered the number of cholesterol-related DEGs significantly increased in the brain due to stress, and exhibited regional heterogeneity. Further investigation of the frontal cortex, a brain region closely related to depression, revealed stress caused significant disruption to key genes related to cholesterol metabolism, including HMGCR, CYP46A1, ACAT1, APOE, ABCA1, and LDLR, leading to an increase in total cholesterol content and a significant decrease in synaptic proteins PSD-95 and SYN. This indicates cholesterol metabolism affects neuronal synaptic plasticity and is associated with stress-induced depressive-like behavior in mice. Adeno-associated virus interference with NR3C1 in the prefrontal cortex of mice subjected to short-term stress resulted in reduced protein levels of NRIP1, NR1H2, ABCA1, and total cholesterol content. At the same time, it increased synaptic proteins PSD95 and SYN, effectively alleviating depressive-like behavior. Therefore, these results suggest that short-term stress may induce cholesterol metabolism disorders by activating the NR3C1/NRIP1/NR1H2 signaling pathway. This impairs neuronal synaptic plasticity and consequently participates in depressive-like behavior in mice. These findings suggest that abnormal cholesterol metabolism in the brain induced by stress is a significant contributor to depression onset.depression; cholesterol metabolism; frontal cortex; NR3C1/NRIP1/NR1H2 pathway.

AGFG1 increases cholesterol biosynthesis by disrupting intracellular cholesterol homeostasis to promote PDAC progression

PurposeCholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored. Experimental DesignThe relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism. ResultsAGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism. ConclusionsOur study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.

Molecular mechanism of renal lipid accumulation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.

Berberine alleviates cholesterol and bile acid metabolism disorders induced by high cholesterol diet in mice

Berberine (BBR) is a traditional Chinese herb with broad antimicrobial activity. Gut microbiota plays an important role in the metabolism of bile acids and cholesterol. Our study investigated the effects of BBR on alleviating cholesterol and bile acid metabolism disorders induced by high cholesterol diet in mice. Adult male C57BL/6J mice fed with high cholesterol diet (HC) containing 1.25 % cholesterol (HC group) or fed with chow diet containing 0.02 % cholesterol (Chow group) served as controls. BBR50 and BBR100 group mice were fed with HC, and oral BBR daily at doses of 50 or 100 mg/kg respectively for 8 weeks. The results showed that BBR could reshape the homeostasis and composition of gut microbiota. The abundance of Clostridium genera was significantly inhibited by BBR, which resulted in a significant reduction of secondary bile acids within the enterohepatic circulation and a significant lower hydrophobic index of bile acids. The absorption of cholesterol in intestine, the deposition of cholesterol in liver and the excretion of cholesterol in biliary tract were significantly inhibited by BBR, which promoted the unsaturation of cholesterol in bile. These findings suggest the potential utility of BBR as a functional food to alleviate the negative effects of high cholesterol diet.

Gallic Acid Can Promote Low-Density Lipoprotein Uptake in HepG2 Cells via Increasing Low-Density Lipoprotein Receptor Accumulation.

Gallic acid (GA) is a type of polyphenolic compound that can be found in a range of fruits, vegetables, and tea. Although it has been confirmed it improves non-alcoholic fatty liver disease (NAFLD), it is still unknown whether GA can improve the occurrence of NAFLD by increasing the low-density lipoprotein receptor (LDLR) accumulation and alleviating cholesterol metabolism disorders. Therefore, the present study explored the effect of GA on LDLR and its mechanism of action. The findings indicated that the increase in LDLR accumulation in HepG2 cells induced by GA was associated with the stimulation of the epidermal growth factor receptor-extracellular regulated protein kinase (EGFR-ERK1/2) signaling pathway. When the pathway was inhibited by EGFR mab cetuximab, it was observed that the activation of the EGFR-ERK1/2 signaling pathway induced by GA was also blocked. At the same time, the accumulation of LDLR protein and the uptake of LDL were also suppressed. Additionally, GA can also promote the accumulation of forkhead box O3 (FOXO3) and suppress the accumulation of hepatocyte nuclear factor-1α (HNF1α), leading to the inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) mRNA expression and protein accumulation. This ultimately results in increased LDLR protein accumulation and enhanced uptake of LDL in cells. In summary, the present study revealed the potential mechanism of GA's role in ameliorating NAFLD, with a view of providing a theoretical basis for the dietary supplementation of GA.

Mechanism of Tougu Xiaotong Capsules in delaying degeneration of osteoarthritis by regulating cholesterol metabolism in chondrocytes through lncRNA MALAT1

From the perspective of lncRNA MALAT1 regulating cholesterol metabolism in chondrocytes, this paper explores the effect and mechanism of Tougu Xiaotong Capsules(TGXTC) in delaying the degeneration of osteoarthritis. After one week of adaptive feeding, 48(8-week-old) C57BL/6 mice were randomly divided into a blank group(12 mice) and a model group(36 mice) by random number table method. The mice in the model group were anesthetized by inhalation of 5% isoflurane, and the OA model was induced by Hulth method. The experiment randomly divided the mice into a model group(12 mice), a drug-positive group(taururso-deoxycholic acid)(12 mice), and a TGXTC group(12 mice). The drug-positive group was given 500 mg·kg~(-1) taurodeoxycholic acid by intragastric administration. TGXTC group was given TGXTC 368 mg·kg~(-1) by gavage. The blank group and model group were given the same amount of normal saline for four weeks. After the intervention, the mice in each group were killed under anesthesia, and the knee cartilage tissue was separated and collected. The morphologic changes of knee cartilage were observed. The level of lncRNA MALAT1 in the cartilage tissue was detected by real-time PCR. The protein expressions of ABCA1, ApoA1, LXRβ, CHOP, and caspase-3 in mouse articular cartilage were detected by Western blot. Lentivirus-coated plasmid was used to transfect mouse chondrocytes with sh-MALAT1. The gene levels of lncRNA MALAT1 in mouse chondrocytes transfected with sh-MALAT1 were detected by real-time PCR. Western blot was used to detect the effect of TGXTC on the protein content of ABCA1, ApoA1, LXRβ, CHOP, and caspase-3 in thapsigargin(TG)-induced mouse chondrocytes after lncRNA MALAT1 knockdown. Flow cytometry was used to detect the effect of TGXTC on apoptosis of TG-induced mouse chondrocytes after lncRNA MALAT1 knockdown. The results of HE and saffranine O staining showed that compared with the model group, the structure of the cartilage layer was basically intact; the damage degree of joint structure was significantly improved, and the cartilage matrix was significantly enhanced by saffranine O staining in the TGXTC group and drug-positive group. Compared with the model group, the lncRNA MALAT1 level was significantly decreased in the TGXTC group and drug-positive group. Compared with the model group, the protein content of ABCA1, ApoA1, and LXRβ was significantly increased, while that of CHOP and caspase-3 in the TGXTC group and drug-positive group significantly decreased. Compared with the TG group, the lncRNA MALAT1 level in the TG+sh-MALAT1 group was decreased. The lncRNA MALAT1 level in the TG+sh-MA-LAT1+TGXTC group was increased compared with the TG+TGXTC group. Western blot results showed that compared with the model group, protein expressions of ABCA1, ApoA1, LXRβ, CHOP, and caspase-3 in the TGXTC group were significantly decreased, after lncRNA MALAT1 knockdown, the regulation and apoptosis of ABCA1, ApoA1, LXRβ, CHOP, and caspase-3 in TG-induced mouse chondrocytes were weakened by TGXTC. TGXTC can improve the disorder of cholesterol metabolism in OA chondrocytes and delay OA degeneration, which is closely related to the regulation of lncRNA MALAT1.

Pu-erh tea partly improved liver cholesterol metabolism disorders in colitis mice via the gut-liver axis

Pu-erh tea partly improved liver cholesterol metabolism disorders in colitis mice <em>via</em> the gut-liver axis

НАСЛЕДСТВЕННЫЕ ЗАБОЛЕВАНИЯ, ПРОТЕКАЮЩИЕ С ПОРАЖЕНИЕМ ПЕЧЕНИ (ЛЕКЦИЯ)

Background. Hereditary liver diseases are a serious problem in all age groups. Diagnosis of the hereditary liver disor-ders in many cases turns out to be difficult, and before final diagnosis, the patient can change more than one doctor and lose time, which can lead to a worsening of the disease. Therefore, the issue of timely diagnosis of hereditary liver diseases remains relevant. The lecture discusses the issues of diagnosing hereditary diseases occurring with liver damage. Both monogenic syndromes and multifactorial diseases are reviewed. Urea cycle disorders, aminoacidopathias and organic acidurias, lysosomal storage diseases, mitochondrial and peroxisomal diseases, disorders of fatty acids β-oxidation, carbohy-drate, lipid and cholesterol metabolism disorders and other diseases are described. The article describes the syndromes of liver disorders that occur in hereditary diseases; presents the combinations of individual syndromes having diagnostic significance. The pathogenetic aspects of the development of hepatic manifestations of hereditary diseases are considered. Conclusion. Symptoms of liver damage are often in the practice of any physician. Most of them are the manifesta-tions of somatic pathology. However, certain combinations of symptoms of liver damage (syndromes) indicate heredi-tary pathology. Therefore, it is extremely important to know the main liver syndromes in specific hereditary diseases, to understand the etiopathogenesis of such disorders and to carry out proper differential diagnosis.

Cholesterol metabolism: physiological regulation and diseases.

Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesteroltransport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.

Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation

Background & aimsDysregulated cholesterol metabolism is the major factor responsible for cholesterol gallstones (CGS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol homeostasis and its inhibitors secure approval for treating various cholesterol metabolic disorders such as hypercholesterolemia and cardiovascular diseases, but its role in CGS remains unclear. Our study aims to clarify mechanisms by which PCSK9 promotes CGS formation and explore the application of the PCSK9 inhibitor, alirocumab, in preventing and treating CGS. Approach & resultsThe expressions of PCSK9 were notably increased in CGS patients' serum, bile, and liver tissues compared to those without gallstones. Moreover, among CGS patients, hepatic PCSK9 was positively correlated with hepatic cholesterol and negatively correlated with hepatic bile acids (BAs), suggesting PCSK9 was involved in disrupted hepatic cholesterol metabolism related to CGS. Mechanistically, in vitro experiments demonstrated that inhibition of PCSK9 enhanced nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Finally, inhibition of PCSK9 prevented CGS formation and dissolved the existing stones in CGS mice by elevating the conversion of cholesterol into BAs through PPARα-mediated CYP7A1 activation. Additionally, serum PCSK9 level may function as a prognostic signature to evaluate the therapeutic efficacy of PCSK9 inhibitors. ConclusionsInhibition of PCSK9 exerts preventive and therapeutic effects on CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs, which highlights the potential of PCSK9 inhibition as a promising candidate for preventing and treating CGS in clinical applications. Impact and implicationsPCSK9 plays a pivotal role in cholesterol metabolism and its inhibitors are approved for clinical use in cardiovascular diseases. Our study observes inhibition of PCSK9 prevents and dissolves CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs. Mechanistically, PCSK9 inhibition enhanced the nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Our study sheds light on the new function and mechanism of PCSK9 in CGS, providing a novel preventive and therapeutic target with potential clinical applications.

Ginsenoside F1 inhibits cholesterol overload in oxidative-damaged cells through SREBP2/HMGCR pathway

To investigate the inhibitory mechanisms of ginsenoside F1 on hydrogen peroxide induced cholesterol metabolism disorder and oxidative stress in HepG2 cells. 1, 1-diphenyl-2-picrylhydrazyl(DPPH) and oxygen radical absorbance capacity(ORAC) tests were used to detect the scavenging effect of ginsenoside F1 on nitrogen and oxygen free radicals. HepG2 cells were treated with 400 μmol/L hydrogen peroxide and pretreated with 10, 20 and 40 μmol/L ginsenoside F1. Mitochondrial membrane potential(MMP) and total cholesterol levels were detected by JC-1 method and cholesterol kit, respectively. The protein expression levels of sterol-regulatory element binding proteins(SREBP2)and 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGCR) in cholesterol synthesis pathway were detected by Western blot. The DPPH clearance rate of ginsenoside F1 was much lower than that of 6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid(Trolox), but the ORAC capability of ginsenoside F1 was stronger, which was comparable to Trolox. The MMP and protein expression of SREBP2 were significantly decreased in injured group(P&lt;0.05). The cholesterol and protein expression of HMGCR were significantly increased(P&lt;0.05). Whereas, compared with the injured group, the MMP and protein expression of SREBP2 were significantly increased after 10, 20 and 40 μmol/L ginsenoside F1 pretreatment of injured cells(P&lt;0.05). The cholesterol level and protein expression of HMGCR were significantly lower than injured group with concentration-dependent decreases(P&lt;0.05). Ginsenoside F1 can protect against hydrogen peroxide induced oxidative stress in HepG2 cells by inhibiting oxygen free radicals and protecting mitochondria. And its mechanism may be related to the intervention of SREBP2/HMGCR pathway in regulating cellular cholesterol anabolism.

4,8-Dicarboxyl-8,9-iridoid-1-glycoside inhibits apoptosis in human osteoarthritis chondrocytes via enhanced c-MYC-mediated cholesterol metabolism in vitro

BackgroundOsteoarthritis (OA) is a degenerative disease related to cholesterol metabolism disorders. However, current therapies for OA are insufficient and no convincing disease-modifying OA drugs exist. Therefore, we aimed to elucidate the mechanism by which borojoa iridoid glycoside (BIG) inhibits chondrocyte apoptosis in OA.MethodsBorojoa pulp was heated to 70 °C, and the main active substance in borojoa, BIG, was extracted by fractionation at an ultraviolet 254-nm absorption peak. Chondrocytes were identified by immunohistochemistry and visualized by immunofluorescence confocal microscopy. The proliferation of chondrocytes cultured with BIG was determined by MTS assay. The apoptosis of chondrocytes cultured with BIG was tested by Annexin V-FITC/PI, and the cytokine, protein, and cholesterol levels in chondrocytes were detected by ELISA, RT‒qPCR, Western blot, and biochemistry analyses. Protein‒protein interactions were verified by a coimmunoprecipitation (Co-IP) assay.ResultsBIG promoted chondrocyte proliferation and reduced apoptosis in vitro. BIG induced an alteration of the total RNA profiles in chondrocytes, and bioinformatic analysis showed that BIG inhibited chondrocyte apoptosis by promoting c-MYC expression; KEGG analysis confirmed that BIG-inhibited apoptosis was enriched in the cell cycle pathway. Flow cell cycle experiments confirmed that BIG promoted chondrocyte proliferation by significantly increasing the S phase cell number. The c-MYC inhibitor 10058-F4 stimulated the increased expression of IL-1β, IL-6, TNF-α, and AGEs and suppressed the cholesterol metabolism, which promoted chondrocyte apoptosis and autophagy. Co-IP analysis showed that BIG promoted the interaction of c-MYC and CH25H, Bcl-2, which suggests that BIG could inhibit chondrocyte apoptosis in part by enhancing c-MYC-mediated cholesterol metabolism.ConclusionsThis study confirmed that BIG promotes chondrocyte proliferation and inhibits apoptosis and autophagy, and BIG improving OA is associated with cholesterol metabolism. The results identify a potential mechanism by which BIG enhances c-MYC-mediated CH25H regulation of cholesterol metabolism in vitro and suggest that BIG might be a promising new drug against OA.

Effectivity of Sukamond Pudding as A Healthy Snack for Hypercholesterolemia Patients

Background: Hypercholesterolemia is a disorder of cholesterol metabolism caused by cholesterol levels in the blood exceeding normal limits. Sukamond Pudding is a pudding made from milk flour, rice bran, and almonds, which contain high fiber, vitamin C, and Vitamin E. This study aims to analyze the effectiveness of giving Sukamond pudding as a healthy snack in hypercholesterolemia sufferers.&#x0D; Method: This type of research is quantitative with a quasi-experimental research design. This research was conducted from December 2022 to January 2023 at the OKU Sekarjaya Health Center. The research sample was selected by systematic random sampling with a total sample of 60 respondents.&#x0D; Result: There was an effect of giving Sukamond as a healthy snack to patients with hypercholesterolemia (p=0.000).&#x0D; Conclusion: The results of statistical tests showed that there was an effect of giving Sukamond as a healthy snack to people with hypercholesterolemia.

Exploring Barriers and Facilitators to Indirect Cascade Screening for Familial Hypercholesteraemia in a Paediatric/Parent Population.

Familial hypercholesteraemia (FH), an inherited disorder of cholesterol metabolism, has a prevalence of 1:250 and an associated 6- to 22-fold increased risk for cardiovascular disease. Despite the prevalence and availability of effective risk-reduction treatments, 90% of at-risk Canadians are undiagnosed. Indirect cascade screening from an index case is useful but the uptake is low (<4%), suggesting that barriers may exist. Using the Theoretical Domains Framework, we sought to determine barriers and facilitators among parents of children diagnosed with FH that may influence the uptake of cascade screening among families. A qualitative description approach was used for virtual interviews with 10 parents of children with FH, recruited from a regional Lipid Clinic in Toronto, Canada. Semistructured interviews were conducted. The data were analysed using a directed content analysis method. Five interconnecting themes were identified that captured both facilitators and barriers of indirect cascade screening: a high level of knowledge about FH after clinic attendance; parents' surprise of their child's diagnosis and ongoing worry; parents' willingness to communicate the need for cholesterol screening; parents' desire for educational materials, dictated by an external vs internal locus of control; and social and societal influences including the lack of awareness about FH in professional and public domains. The themes identified will inform next steps in programme development. An urgent need was identified for strategies to educate the public and primary care providers about FH and blood cholesterol/genetic screening.

Subclinical ketosis leads to lipid metabolism disorder by downregulating the expression of acetyl-coenzyme A acetyltransferase 2 in dairy cows

Ketosis is a metabolic disease that often occurs in dairy cows postpartum and is a result of disordered lipid metabolism. Acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2) is important for balancing cholesterol and triglyceride (TG) metabolism; however, its role in subclinical ketotic dairy cows is unclear. This study aimed to explore the potential correlation between ACAT2 and lipid metabolism disorders in subclinical ketotic cows through in vitro and in vivo experiments. In the in vivo experiment, liver tissue and blood samples were collected from healthy cows (CON, n = 6, β-hydroxybutyric acid [BHBA] concentration <1.0 mM) and subclinical ketotic cows (subclinical ketosis [SCK], n = 6, BHBA concentration = 1.2-3.0 mM) to explore the effect of ACAT2 on lipid metabolism disorders in SCK cows. For the in vitro experiment, bovine hepatocytes (BHEC) were used as the model. The effects of BHBA on ACAT2 and lipid metabolism were investigated via BHBA concentration gradient experiments. Subsequently, the relation between ACAT2 and lipid metabolism disorder was explored by transfection with siRNA of ACAT2. Transcriptomics showed an upregulation of differentially expression genes during lipid metabolism and significantly lower ACAT2 mRNA levels in the SCK group. Compared with the CON group in vivo, the SCK group showed significantly higher expression levels of peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulator element binding protein 1c (SREBP1c) and significantly lower expression levels of peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl-transferase 1A (CPT1A), sterol regulatory element binding transcription factor 2 (SREBP2), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Moreover, the SCK group had a significantly higher liver TG content and significantly lower plasma total cholesterol (TC) and free cholesterol content. These results were indicative of TG and cholesterol metabolism disorders in the liver of dairy cows with SCK. Additionally, the SCK group showed an increased expression of perilipin-2 (PLIN2), decreased expression of apolipoprotein B, and decreased plasma concentration of very low-density lipoproteins (VLDL) and low-density lipoproteins cholesterol (LDL-C) by downregulating ACAT2, which indicated an accumulation of TG in liver. In vitro experiments showed that BHBA induced an increase in the TG content of BHEC, decreased content TC, increased expression of PPARγ and SREBP1c, and decreased expression of PPARα, CPT1A, SREBP2, and HMGCR. Additionally, BHBA increased the expression of PLIN2 in BHEC, decreased the expression and fluorescence intensity of ACAT2, and decreased the VLDL and LDL-C contents. Furthermore, silencing ACAT2 expression increased the TG content; decreased the TC, VLDL, and LDL-C contents; decreased the expression of HMGCR and SREBP2; and increased the expression of SREBP1c; but had no effect on the expression of PLIN2. These results suggest that ACAT2 downregulation in BHEC promotes TG accumulation and inhibits cholesterol synthesis, leading to TG and cholesterol metabolic disorders. In conclusion, ACAT2 downregulation in the SCK group inhibited cholesterol synthesis, increased TG synthesis, and reduced the contents of VLDL and LDL-C, eventually leading to disordered TG and cholesterol metabolism.

In silico discovery of food-derived phytochemicals against asialoglycoprotein receptor 1 for treatment of hypercholesterolemia: Pharmacophore modeling, molecular docking and molecular dynamics simulation approach

Hypercholesterolemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). Successful management of cholesterol metabolism disorders can prevent these ASCVD effectively. Asialoglycoprotein receptor 1 (ASGR1) is the main subtype of sialoglycoprotein receptor, which is specifically expressed in the liver and mediates the endocytosis of blood asialoglycoprotein to lysosome degradation. Recently, ASGR1 has been reported as a new therapeutic target for the treatment of hypercholesterolemia. In this study, the main aim was to identify natural ASGR1 inhibitors from plant food chemicals library through pharmacophore and docking based virtual screening. Total 14 phytochemicals of potential ASGR1 inhibitors were identified, which presented docking affinity higher than control compound through docking based virtual screening. The docking pose showed the top three hits interacted residues were located at active pocket of ASGR1 with hydrogen bonds, hydrophobic interactions and electrostatic interactions. The top three hits (ZINC85664954, ZINC169372863, and ZINC195764535) were then subjected to 200 ns molecular dynamics simulation to evaluate the stability of docked complexes. These results showed that selected phytochemicals bound to ASGR1 with higher stability than control compound. Binding free energy of each docked complex was calculated by the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. The binding free energy of ZINC85664954, ZINC169372863, ZINC195764535, and control-ASGR1 docked complexes were −18.359, −13.303, −14.389, and −6.229 kcal/mol, respectively. This indicated that selected hits bound to ASGR1 with higher affinity than control compound. Network pharmacology analysis shows that these phytochemicals have obvious multiple-effects and can regulate various biochemical pathways related to hypercholesterolemia. Besides, selected phytochemicals have suitable pharmacokinetics properties, suggesting that these compounds may be potential drug candidates. This study may be contributed to rational design of novel ASGR1 inhibitors for treatment of hypercholesterolemia.

Apolipoprotein E deficiency potentiates macrophage against Staphylococcus aureus in mice with osteomyelitis via regulating cholesterol metabolism.

Staphylococcus aureus (S. aureus) osteomyelitis causes a variety of metabolism disorders in microenvironment and cells. Defining the changes in cholesterol metabolism and identifying key factors involved in cholesterol metabolism disorders during S. aureus osteomyelitis is crucial to understanding the mechanisms of S. aureus osteomyelitis and is important in designing host-directed therapeutic strategies. In this study, we conducted in vitro and in vivo experiments to define the effects of S. aureus osteomyelitis on cholesterol metabolism, as well as the role of Apolipoprotein E (ApoE) in regulating cholesterol metabolism by macrophages during S. aureus osteomyelitis. The data from GSE166522 showed that cholesterol metabolism disorder was induced by S. aureus osteomyelitis. Loss of cholesterol from macrophage obtained from mice with S. aureus osteomyelitis was detected by liquid chromatography-tandem mass spectrometry(LC-MS/MS), which is consistent with Filipin III staining results. Changes in intracellular cholesterol content influenced bactericidal capacity of macrophage. Subsequently, it was proven by gene set enrichment analysis and qPCR, that ApoE played a key role in developing cholesterol metabolism disorder in S. aureus osteomyelitis. ApoE deficiency in macrophages resulted in increased resistance to S. aureus. ApoE-deficient mice manifested abated bone destruction and decreased bacteria load. Moreover, the combination of transcriptional analysis, qPCR, and killing assay showed that ApoE deficiency led to enhanced cholesterol biosynthesis in macrophage, ameliorating anti-infection ability. We identified a previously unrecognized role of ApoE in S. aureus osteomyelitis from the perspective of metabolic reprogramming. Hence, during treating S. aureus osteomyelitis, considering cholesterol metabolism as a potential therapeutic target presents a new research direction.

Large polystyrene microplastics results in hepatic lipotoxicity in mice

Like small microplastics (MPs), recent studies reveal that large MPs could cause health risks in mice, even if they are not enriched in tissues. However, potential hepatoxicity following large MPs exposure and the underlying mechanisms have not been thoroughly investigated. In the present study, we explored the disruption of hepatic lipid metabolism and potential underlying toxic mechanisms in mice caused by long-term exposure to large polystyrene MPs (40–100 μm) based on a multi-omic approach. After 21 weeks of feeding foods containing MPs (50 and 500 mg/kg food), lipidomic revealed that environmentally relevant and higher doses MP exposures resulted in significant changes in a total of 20 lipid classes. Ceramide (Cer) and dihydroceramide (dhCer) were significantly reduced, while cholesteryl ester (CE), lysoalkylphosphatidylcholine (LPCO), lysophosphatidylethanolamine (LPE) and total glyceride (TG) were all elevated by MPs. The transcriptomic and other physiological data suggested that the potential toxic mechanisms may be related to disorders of fatty acid and cholesterol synthesis and metabolism disorders, and transporting of TG. Our findings demonstrate the hepatic lipotoxicity following exposure to environmentally relevant and higher doses of large MPs, calling for future research and management of the environmental risks of MPs with relatively large particle sizes.

MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly.

MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date. The disorder is caused by missense variants in the MSMO1 gene encoding methylsterol monooxygenase 1, leading to the accumulation of methylsterols. Clinically, MSMO1 deficiency is characterized by growth and developmental delay, often in association with congenital cataracts, microcephaly, psoriasiform dermatitis and immune dysfunction. Treatment with oral and topical cholesterol supplements and statins was reported to improve the biochemical, immunological, and cutaneous findings, supporting a potential treatment following the precision diagnosis of MSMO1 deficiency. We describe two siblings from a consanguineous family presenting with novel clinical features of polydactyly, alopecia and spasticity. Whole-exome sequencing revealed a novel, homozygous c.548A > C, p.(Glu183Ala) variant. Based on previously published treatment algorithms, we initiated a modified dosage regime with systemic cholesterol supplementation, statins and bile acid along with topical application of a cholesterol/statin formulation. This resulted in a marked improvement of psoriasiform dermatitis and some hair growth.