Rosa roxburghii Tratt pomace, is a juice extraction rich in polyphenols with strong antioxidant activity. The objective of this study was to evaluate the effect of fermented Rosa roxburghii Tratt pomace (FRRT) on growth performance, plasma biochemistry and antioxidant status, and longissimus dorsi muscle amino- and fatty-acid profiles in meat goats. Twenty-four goats with similar body weights (30.7 ± 4.71 kg) were allotted in a completely randomized design to either basal diet (CON) or the same diet containing 7% (LF) or14% (HF) of FRRT on a total mixed ration (TMR) dry matter (DM) basis for 60 d following 14 d adaptation. FRRT did not alter dry matter intake or average daily weight gain, but reduced (P < 0.05) the feed conversion ratio (FCR) compared to CON. Plasma creatinine and total cholesterol increased (P < 0.05) with FRRT, while low-density lipoprotein cholesterol (LDL-C) was numerically higher in the HF group (overall P = 0.069). FRRT increased (P < 0.05) the plasma total antioxidant capacity and catalase; malondialdehyde tended to be lower (P = 0.067) HF group than CON. In muscle, the 14% FRRT diet increased essential, non-essential, flavor and total amino acids (P < 0.05), with higher concentrations of several individual amino acids (e.g., threonine, serine, glycine, tyrosine, lysine, arginine). Among fatty acids, C15:0 decreased in 7% FRRT (P < 0.05) and arachidonic acid (C20:4n-6) increased (P < 0.05), whereas sums of SFA, MUFA and PUFA did not differ. In conclusion, 7–14% FRRT (DM basis) improved feed efficiency and antioxidant status and favorably modified selected muscle amino- and fatty-acid traits, but elevated circulating cholesterol; the lipid responses warrant further study.

Atherosclerotic cardiovascular disease, characterized by an imbalanced lipid metabolism and a dysregulated immune response, is a major cause of death worldwide. The AhR (aryl hydrocarbon receptor) is a ligand-activated transcription factor that is highly expressed in the liver and primarily known for its role in detoxification. However, recent studies suggest that the AhR also plays a key role in immune regulation, indicating that this receptor can influence the development of atherosclerosis. Apoe-/- and Apoe-/-Ahr-/- mice were fed a western-type diet for 12 weeks to induce atherosclerosis. Aortic roots were analyzed for size and composition of atherosclerotic plaques. Plasma samples were characterized for inflammation and lipid levels. Liver samples were analyzed for cytokines and lipid accumulation and subjected to RNA sequencing and kinomics. A PheWAS (Phenome-Wide Association Study) was performed to identify associations of genetic AHR variants with atherosclerotic cardiovascular disease and lipid phenotypes in humans. The number of circulating leukocytes was increased in Apoe-/-Ahr-/- mice compared with Apoe-/- controls. Surprisingly, however, mice lacking Ahr showed significantly smaller plaques than Apoe-/- mice, which coincided with strongly reduced plasma cholesterol and triglyceride levels. The liver lipid levels showed a similar effect, indicating a key role of the AhR in lipid metabolism. RNA sequencing of the liver revealed that lipid metabolism pathways were particularly impacted in Apoe-/-Ahr-/- mice. Furthermore, through kinomics, we identified signaling pathways affected by the absence of Ahr. PheWAS analysis revealed significant associations between the AHR variant rs4410790 and lipid traits, including plasma triglycerides, LDL (low-density lipoprotein), and total cholesterol. Our study demonstrates a remarkable role for AhR in the pathogenesis of atherosclerosis, interfering with both lipid metabolism and inflammatory pathways. Although the underlying mechanisms remain unclear, these results demonstrate a novel and crucial role for AhR in atherosclerotic cardiovascular disease.

This study investigated the effects of different dietary flaxseed inclusion levels (0, 2, 4, 6, 8, and 10%) on the fatty acid composition, plasma biochemical parameters, and meat quality of Beijing-you chickens. A total of 960 6-week-old birds were randomly assigned to six dietary treatments in a completely randomized design, with eight replicates per treatment. Dietary flaxseed supplementation significantly decreased plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and triglyceride (TG) concentrations (p &lt; 0.05), while significantly increasing high-density lipoprotein cholesterol (HDL-C) levels (p &lt; 0.05). Meat quality was also improved, as evidenced by reduced drip loss (p &lt; 0.05). Moreover, gas chromatography analysis revealed that increasing dietary flaxseed levels markedly elevated the concentrations of total ω-3 polyunsaturated fatty acids (ω-3 PUFAs) in both breast and leg muscles (p &lt; 0.05), accompanied by a significant reduction in the ω-6/ω-3 ratio (p &lt; 0.05). Dietary flaxseed supplementation did not significantly affect the docosahexaenoic acid (DHA) content in pectoral muscle (p &gt; 0.05), with the highest value observed at the 6% inclusion level. In conclusion, dietary flaxseed supplementation effectively enriches ω-3 PUFAs in chicken meat while simultaneously enhancing metabolic health indicators and improving meat quality traits.

The PCSK9-LDLR interaction, driving elevated LDL-C, is a key driver of ASCVD pathogenesis. Identifying peptides disrupting this interaction offers an alternative ASCVD therapy. Herein, via structure-based virtual screening with Pep2-8 as a control, we identified TPP-4, a high-affinity peptide inhibitor targeting PCSK9. Compared to Pep2-8, TPP-4 showed lower binding free energy (approximately −9.8 kcal/mol) and K d values (K d = 0.08 ± 0.01 μM), interacting with PCSK9’s LDLR-binding domain through multiple interactions. CD spectroscopy also provided indirect evidence for these key interactions. Additionally, it stably bound to the LDLR binding domain of PCSK9 during 100 ns MD simulations. It showed good serum stability, negligible HepG2 cytotoxicity, and restored surface LDLR (EC50 = 1.12 ± 0.05 μM). In mice, TPP-4 upregulated hepatic LDLR and reduced plasma total cholesterol levels. In conclusion, these data demonstrate that TPP-4 could be a high-affinity and potent candidate peptide for ASCVD treatment.

Background and aims: Apolipoprotein E (ApoE) is a key regulator of lipid metabolism, controlling transport and clearance of triglyceride rich lipoproteins. Although ApoE is produced in several tissues, the liver, especially hepatocytes, is the main source of circulating ApoE. Whole body ApoE knockout mice develop severe dyslipidemia, whereas mice lacking ApoE only in hepatocytes (ApoEΔHep) display only mild alterations on a standard diet, suggesting compensation from extrahepatic sources and raising questions about the specific contribution of hepatic ApoE. This work investigated the distinct role of hepatocyte derived ApoE in hepatic lipid handling. Methods: ApoEΔHep mice were generated by crossing ApoE flox/flox mice with Albumin Cre mice. Animals were kept on a standard chow diet for 12 weeks. Lipid metabolism was assessed by FPLC, Western blotting, hepatic gene expression analysis and functional assays of lipoprotein production and clearance. Results: Plasma WB confirmed that hepatocyte-derived ApoE is the main circulating source of the protein, which was absent in ApoEΔHep mice. Total plasma cholesterol was similar to controls under both standard diet (76,199,99 vs. 85,6415,20 mg/dL) and high cholesterol diet (154,726,45 vs. 151,414,35 mg/dL). However, lipoprotein profiling revealed a shift toward LDL enriched cholesterol in ApoEΔHep mice, in contrast to the VLDL dominant pattern of global ApoE KO mice. ApoEΔHep animals showed delayed clearance of triglycerides, consistent with impaired removal of triglyceride rich lipoproteins, and a 46% reduction (p &lt; 0.0001) in VLDL production, indicating a role for hepatocyte ApoE in the synthesis and secretion of these particles. Hepatic transcript analysis pointed to deregulated lipid metabolic pathways. Conclusions: This work highlights a dual role of hepatocyte-derived ApoE in both the production and clearance of TG-rich lipoproteins, pointing to distinct function of ApoE at systemic versus hepatocellular level. Ongoing molecular analyses aim to further dissect the intracellular mechanisms of lipoprotein synthesis and clarify the hepatocyte-specific contributions of ApoE to lipid metabolism and dyslipidemia.

Associations of individual nutrient and non-nutrient factors on endocrine and metabolic parameters in neonatal calves fed colostrum from their own dams.

High blood cholesterol levels are recognized as an important risk factor for dementia, including Alzheimer's disease (AD). Although the mechanisms linking high cholesterol to cognitive decline remain unclear, blood-brain barrier dysfunction and neuroinflammation appear to connect cholesterol dishomeostasis to brain disorders. Previous studies have shown that elevated blood cholesterol levels can activate microglia, modulating its reactivity in the central nervous system. Therefore, this study aims to investigate the role of microglial reactivity in cognitive impairments associated with sporadic hypercholesterolemia. To generate an animal model of sporadic hypercholesterolemia, male and female adult CF-1 mice were fed a high-cholesterol diet (2.5% of cholesterol and cholic acid 0.5%), whereas control mice were fed a normal diet for eight weeks. In the last four weeks, mice were concomitantly treated by oral gavage (once a day) with minocycline, a pharmacological modulator of microglia reactivity. Mice fed a cholesterol-rich diet for eight weeks showed a significant increase in total plasma cholesterol levels and impaired performance in hippocampal-dependent memory tasks. Interestingly, minocycline treatment improved hypercholesterolemic mice performance in memory tasks. The memory deficits associated with sporadic hypercholesterolemia were accompanied by a decreased number of lectin-positive cells and a reduced presence of microglia in the hippocampal perivascular area, a process that was not influenced by minocycline treatment or sex. Interestingly, minocycline treatment increased Claudin-5 immunocontent in the prefrontal cortex and hippocampus of hypercholesterolemic mice. However, no significant changes in microglial density or morphology were observed in these brain regions, regardless of pharmacological intervention or sex. Taken together, our results demonstrate that sporadic hypercholesterolemia in mice was accompanied by deficits in hippocampal-dependent memory tasks and a reduction in microglial presence in the perivascular area. Notably, minocycline treatment improved memory in hypercholesterolemic mice and increased Claudin-5 immunocontent without altering microglial density or morphology or their presence in the perivascular area. No significant sex differences were observed, indicating that the effects of sporadic hypercholesterolemia in mice are consistent across sexes.

Roles of garlic and its bioactive compounds in modulating cholesterol metabolism.

Nanosphere loaded with curcumin attenuates adipogenesis and lipid metabolism by modulating AKT/mTORC1/PPARγ phosphorylation.

BackgroundThis study investigates the combined effects of time-restricted eating (TRE) and Tai Chi exercise (EX) on glycolipid metabolism and endothelial function in postmenopausal women, a population at heightened risk of metabolic and vascular disorders.Materials and MethodsA total of 142 postmenopausal women aged 50–60 years were randomly assigned to one of three groups: TRE combined with Tai Chi (TRE + EX, n = 47), TRE alone (n = 47), or a control group with conventional lifestyle (CON, n = 48). The TRE protocol required participants to consume all meals within an 8-hour window for 8 weeks, while the EX protocol involved three weekly 60-minute sessions of Yang-style 24-form Tai Chi. Outcomes included glycolipid markers, such as fasting plasma glucose, total cholesterol (Tot-Chol), and low-density lipoprotein cholesterol (LDL-C), as well as endothelial function assessed by flow-mediated dilation (FMD), nitric oxide (NO), and endothelin−1 (ET−1).ResultsSignificant group-by-time interactions were observed for Tot-Chol (p = 0.001) and LDL-C (p = 0.003), with the TRE + EX group showing the largest reductions compared to the TRE group (p = 0.030; p = 0.003) and the CON group (p = 0.000; p = 0.050). For FMD, a significant interaction was also observed (p = 0.003). Both the TRE + EX group and the TRE group showed significant improvements in FMD compared to baseline (p = 0.005; p = 0.044). However, only the TRE + EX group demonstrated significantly higher FMD than the CON group (p = 0.003).ConclusionThe combination of TRE and Tai Chi was more effective in improving lipid profiles and endothelial function than TRE alone. These findings highlight the potential of integrating dietary timing with structured exercise as a strategy for enhancing metabolic and vascular health in postmenopausal women.

Background: Monocyte-derived macrophages play key roles in both the initiation and progression of atherosclerosis, an underlying cause of the majority of cardiovascular diseases. Previous investigations reported significant contributions of various secretory matricellular proteins in the pathogenesis of atherosclerosis. In our recent study, we observed elevated levels of a matricellular protein R-spondin 2 (RSPO2) in human and murine atherosclerotic arteries. Furthermore, RSPO2 expression was detected in lesional macrophages of atherosclerotic arteries. Additional experiments revealed increased RSPO2 levels in mouse primary macrophages exposed to atherogenic oxidized LDL compared with control cells. However, the role of macrophage RSPO2 in atherosclerosis development remains unknown. Methods and Results: We generated novel myeloid cell-specific Rspo2 knockout mice ( Rspo2 F/F LysM Cre +/- ; Rspo2 ΔM ) by crossing Rspo2 F/F and LysM Cre +/- mice. Eight-week-old male Rspo2 ΔM and littermate control Rspo2 F/F mice were injected intraperitoneally with AAV8-h PCSK9 and fed a Western diet for 16 weeks to induce hypercholesterolemia and atherosclerosis. No differences in various metabolic parameters, including body weight, whole-body fat/lean mass, fasting blood glucose, and plasma total cholesterol, were observed between the two groups after Western diet feeding. Histochemical staining performed on aortic root sections (at least 4 sections/mouse spaced 70-90 µm apart) demonstrated increased neointimal lesions (H&amp;E) and elevated lipid deposition (Oil red O) in Rspo2 ΔM mice compared with controls. However, aortic root lesional collagen content (Masson’s Trichrome) and macrophage accumulation (CD68 + cells) were comparable between control and myeloid cell-restricted Rspo2 -deficient mice. In vitro experiments performed with peritoneal macrophages (CD11b + Ly6G - Ly6C + ) showed increased uptake of fluorescently-labeled oxidized LDL and elevated inflammation in Rspo2 ΔM cells compared with controls, with no differences in cholesterol efflux capacities. Conclusion: These findings indicate that myeloid cell Rspo2 deletion promotes atherosclerosis by stimulating macrophage lipid uptake and promoting cellular inflammation. Collectively, these results identify myeloid cell Rspo2 as a suppressor of atherosclerosis.

Background and aims: Regression of pre-existing atherosclerotic vascular disease has only been observed with aggressive lipid lowering therapy. Therefore, the aim of the present study is to evaluate the effect of the novel cholesterol ester transfer protein (CETP) inhibitor obicetrapib in combination with the intestinal cholesterol absorption inhibitor ezetimibe on top of high dose atorvastatin as a potent combination for regression of established atherosclerosis in APOE*3Leiden.CETP mice, a translational mouse model for hyperlipidemia and atherosclerosis. Methods: Female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet (WTD) with 0.3% w/w cholesterol for 12 weeks to induce atherosclerosis. Hereafter, an initial/baseline control group was sacrificed and the remaining mice were divided into 4 groups and treated with WTD with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing atorvastatin (5 mg/kg bw/d), obicetrapib (2 mg/kg/day) + ezetimibe (0.6 mg/kg/day) or the combination of atorvastatin, obicetrapib and ezetimibe for 24 weeks. Effects on plasma lipids and atherosclerotic lesion size were assessed. Results: After 24 weeks of treatment atorvastatin alone, the combo treatment of obicetrapib + ezetimibe and the triple combo treatment of obicetrapib + ezetimibe + atorvastatin reduced total plasma cholesterol levels (-40%, -58% and -76%, all p&lt;0.001; respectively), mainly attributed to a decrease in non-HDL-C levels (-41%, -73% and -88%, all p&lt;0.001; respectively). Triple combo treatment decreased non-HDL-C to 50 mg/dL. Obicetrapib + ezetimibe combo and the triple combo treatment nearly completely blocked CETP activity resulting in increased HDL-C levels (+161% and +95%, all p &lt;0.001; respectively). Mono-treatment with atorvastatin reduced progression of atherosclerosis (-28%, p=0.001, versus control) and the obicetrapib + ezetimibe combo treatment completely blocked progression. Obicetrapib + ezetimibe + atorvastatin triple combo treatment regressed lesion size as compared to baseline (-44%, p=0.032), thereby diminishing lesion severity and increasing the lesion-free area. Compared to atorvastatin monotreatment, triple combo treatment further reduced lesion size (-60%, p&lt;0.001). Conclusions: High-intensive cholesterol-lowering triple combo treatment with obicetrapib + ezetimibe on top of atorvastatin robustly decreases non-HDL-C and regresses atherosclerotic lesion area in APOE*3Leiden.CETP mice.

ApoB-100 and apo(a) levels in healthy blood donors by ABO blood type.

This study aims to investigate the optimal dose ratio and mechanisms of the primary active components in Yinchenhao decoction (geniposide, chlorogenic acid, and rhubarb polysaccharides) for ameliorating metabolic-associated steatotic liver disease (MASLD). C57BL/6 mice were randomly divided into the normal control group, model control group, uniform design groups 1-6, and Yinchenhao Decoction group; except for the normal control group, mice in all other groups were fed a Western diet to establish a MASLD model, and after 8 weeks of modeling, mice in the uniform design groups 1-6 and Yinchenhao Decoction group were given the corresponding drugs by gavage. At 12 weeks, all mice were sacrificed: their body weight and liver weight were measured, hematoxylin-eosin staining was used to observe the histopathological changes of liver tissue, the plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST) were detected, and the levels of total cholesterol (TC) and triglycerides (TG) in plasma and liver were measured. Based on these results, the optimal uniform design group was identified; subsequently, with plasma AST, plasma TG, and liver TC levels as screening indicators, the optimal dose ratio was obtained via a regression equation, which was further verified from two dimensions, namely functional indicators and tissue morphology. Meanwhile, glucose tolerance test and insulin tolerance test were conducted to evaluate glucose metabolic homeostasis and insulin sensitivity in mice, periodic acid-Schiff staining was used to observe glycogen accumulation, quantitative reverse transcription-polymerase chain reaction was employed to detect the mRNA expression of genes related to glycolipid metabolism and bile acid metabolism, Western blotting was performed to measure the protein expression of molecules involved in bile acid metabolism, and commercial kits were used to determine the plasma levels of total bilirubin (TBIL), direct bilirubin (DBIL), and total bile acid (TBA). Combinations of geniposide, chlorogenic acid, and rhubarb polysaccharide all reduced the liver-to-body weight ratio, alleviated liver injury, and decreased lipid accumulation, among which the uniform design group 6 (200 mg/kg geniposide+160 mg/kg chlorogenic acid+340 mg/kg rhubarb polysaccharide) exhibited the optimal efficacy. Meanwhile, regression analysis indicated that the dosage ratio of uniform design group 6 was the optimal one for MASLD intervention. Validation experiments showed that, compared with single-drug intervention, the optimal dosage ratio resulted in significantly lower body weight, as well as lower plasma levels of ALT, AST and TC in mice (all P<0.05), along with a more pronounced reduction in the area of hepatic lipid accumulation. Mechanistic investigation experiments demonstrated that intervention with the optimal dosage ratio significantly improved glucose tolerance and insulin sensitivity in mice (all P<0.05), reduced hepatic glycogen deposition, and downregulated the mRNA expression of glycolipid metabolism-related genes such as Gsk3, G6pc, Pck1, Fbp1, Fasn, Srebp-1c, Scd1, Slc27a2, and Slc27a5 (all P<0.05); it also decreased plasma levels of TBIL, DBIL, and TBA (all P<0.05), reversed the abnormal protein expression of bile salt export pump (BSEP), farnesoid X receptor (FXR), and cholesterol-7α-hydroxylase (CYP7A1) in the liver (all P<0.05), and reversed the abnormal mRNA expression of bile acid metabolism-related genes including Nr1h4, Cyp7a1, Cyp27a1, Slc10a1, and Slco1a1 (all P<0.05). The combination of geniposide (200 mg/kg), chlorogenic acid (160 mg/kg), and rhubarb polysaccharide (340 mg/kg) exerts the optimal ameliorative effect on MASLD in mice. This superior efficacy is presumably achieved by synergistically regulating the key nodes of glycolipid metabolism and bile acid metabolism, ultimately optimizing the therapeutic outcome.

Lymphatic filariasis results in chronic edema, pain, elephantiasis and disfigurement in humans. It was previously reported that platelet aggregation is inhibited in lymphatic filariasis patients, compared to healthy controls. However, it was not clear whether the inhibition was due to filarial parasite infection or due to the presence of edema. This study was planned to compare platelet functions, plasma proteins and lipids in filarial and non-filarial edema patients. Edema patients were tested for the presence of filarial antigens and antibodies in their blood and were grouped as filarial and non-filarial edema patients accordingly. Platelet aggregation, size distribution, platelet activation markers, plasma proteins and lipids were measured in collected blood samples. Results showed that platelet aggregation was significantly inhibited in filarial edema patients, compared to non-filarial edema patients. Soluble P-selectin and beta thromboglobulin showed significant positive correlation with each other only in non-filarial edema patients. Plasma total cholesterol was lower in filarial edema patients, and HDL was lower in only female filarial edema patients. Observations confirm that inhibition of platelet functions is due to filarial parasite infection, not merely due to the presence of edema. Results also indicate uncoupling and disturbances of platelet activation processes.

IntroductionBangpungtongsung-san (BTS) is a traditional multi-herb preparation prescribed for obesity, but its role in obesity-associated depression remains unclear. We evaluated whether BTS alleviates depressive-like behaviors in high-fat diet (HFD) induced obese mice and elucidated the underlying mechanisms of its antidepressant potential.MethodsMale C57BL/6N mice were randomized to normal diet (ND) or continuous HFD and maintained for 10 weeks. Throughout this period, mice were orally treated with BTS (30, 100, or 300 mg/kg), fluoxetine (FXT), simvastatin (SIM), or vehicle under identical chronic regimens. Body weight was monitored weekly. At week 10, metabolic parameters (blood glucose, plasma total cholesterol, triglycerides, HDL-C, and leptin) and depressive-like behaviors (tail suspension test and forced swimming test) were assessed. Subsequently, mechanistic analyses were performed to determine the effects of BTS on systemic and brain inflammatory responses, BDNF signaling, NMDAR expression, and serotonin (5-HT) signaling (Ido1, Tph2, and SERT) in the prefrontal cortex (PFC) and hippocampus (HPC).ResultsA 10-week continuous HFD feeding produced robust weight gain, hyperglycemia, and elevated levels of total cholesterol (TCHO), triglycerides (TG), HDL-C, and leptin. Oral BTS treatment attenuated body weight gain and reversed these HFD-induced metabolic abnormalities (TCHO, TG, HDL-C, and leptin) in blood. Behaviorally, BTS-treated mice exhibited reduced immobility time compared to HFD group, indicating antidepressant-like effects. Mechanistically, BTS reduced systemic and brain pro-inflammatory cytokines (IL-1β and TNF-α) and normalized hippocampal GluN1/GluN2A/GluN2B protein levels together with BDNF expression restoration. BTS also elevated whole-brain 5-HT and tended to regulate SERT expression in HPC, supporting the enhanced synaptic 5-HT availability. Under identical chronic oral conditions, FXT showed partial antidepressant efficacy with minimal metabolic benefits, whereas SIM exhibited moderate metabolic improvements with limited behavioral effects. Comparatively, BTS provided superior therapeutic outcomes across both behavioral and metabolic parameters.ConclusionBTS ameliorated depression-like behaviors and metabolic dysfunction in HFD-induced obesity through coordinated modulation of inflammation, BDNF signaling, NMDAR expression, and 5-HT neurotransmission in the HPC. These findings support BTS as a promising multi-target candidate for treating comorbid depression and obesity.

The chimeric cytokine IC7Fc conveys the metabolic signaling properties of the glycoprotein 130 receptor cytokines interleukin-6 and ciliary neurotrophic factor via membrane-bound signaling. IC7Fc was previously shown to slow the progression of type 2 diabetes mellitus, and here, we demonstrate its effect on atherosclerotic development. In APOE*3-Leiden.CETP mice, an atherosclerosis-prone model with a humanized lipoprotein metabolism, IC7Fc markedly lowered plasma triglyceride and total cholesterol levels. This was mechanistically explained by an inhibition of de novo lipogenesis in the liver, increased synthesis of bile acids from cholesterol, and down-regulated apolipoprotein B synthesis, which resulted in decreased cholesterol secretion in very low–density lipoprotein particles. As a consequence, IC7Fc treatment considerably reduced atherosclerotic lesion formation and vascular inflammation compared with current antihyperlipidemic therapy. In conclusion, IC7Fc is a promising pharmacological treatment for cardiometabolic diseases targeting hyperlipidemia and inflammation.

Abstract Background and Aims CKD patients are generally considered to be heterogeneous. Younger population can have their CKD as a result of glomerulonephritis, hereditary nephropathy, field workers under frequent dehydration, and so on. Contrarily, the elder population can have their CKD from many different causes such as arteriosclerosis, heart failure, and ethanol abuse. Many kidney diseases can have a rapid deterioration in eGFR even without proteinuria. The progression of CKD needs to be predicted on each patient basis but such prediction method is not readily available especially when proteinuria is absent. Plasma uric acid (UA) level is known to be associated not only with gouty attacks and urolithiasis but also with CKD progression and higher cardiovascular mortality. The author has previously shown that CKD patients with wide fluctuations in plasma UA level are prone to have faster decline in eGFR [2024 ASN Kidney Week]. This study was done whether plasma UA level and/or its fluctuation might serve as a predictive marker for eGFR decline. Method A hospital-wide study with all the laboratory data for a period of 4 years and 2 months was conducted. All the patients with an age 18 or more in whom the eGFR slope was calculated over 731 days or more were included in the study. Medians were used for each datum, including dipstick proteinuria and hematuria (both changed to numeric variables, e.g., 1+ to 1.0). The survey population was divided into "High" and "Low" (the patients with the higher-than-median plasma UA levels vs the rest with the lower levels), as well as into "Wide" and "Stable" (those with the wider- vs the narrower-than-median fluctuations measured as coefficient of variation (CV)). Statistical analysis was done with R 3.6.3 on Ubuntu, with packages including {mice} (imputation for missing values) and {randomForest} (random forest). Results A total of 6,585 patients were included in the study, with an age 65.1 (16.1) years, male:female 3,350:3,235, plasma uric acid 5.31 (1.42) mg/dL, and eGFR 68.9 (20.1) mL/min/1.73 m2. Using "random forest" analysis, one of the multivariate analyses using machine learning, was performed in order to identify factors with the highest importance, i.e., with the largest changes in Gini indices. The factors with high importance in eGFR slope included plasma UA level fluctuation, eGFR, total cholesterol, haemoglobin, plasma UA, alanine transferase, and age, as a descending order of importance. Degree of proteinuria was found to have much less importance than the parameters above. UA fluctuation was found to have the largest contribution to eGFR slope among all. The slope of eGFR was the fastest in "Low and Wide" group, then in "High and Wide" and "High and Stable," and the slowest in "Low and Stable" (−1.51, −1.45 , −1.32 and −1.26 mL/min/1.73 m2/yr, median). Interestingly, "High &amp; Stable" populations were found to be totally different from "Low and Wide" patients; the former, compared with the latter, were younger, less anemic, with better eGFR while higher serum creatinine, with elevated alanine transferase, and higher total cholesterol and serum albumin, shown by both the random forest analysis and t-tests (parameters above were all statistically significant). Conclusion Plasma UA can be an easy, useful marker to predict worse renal prognosis, as a stably high plasma UA level for younger generations as well as wider UA fluctuation for elderly population.

Backgroundβeta-2 glycoprotein I (β2GPI, Apolipoprotein H) is a plasma glycoprotein best known as a major autoantigen in autoimmune disorders such as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), both of which confer elevated cardiovascular risk. Despite its prominence in autoimmunity, its role in lipid metabolism and potential sex-specific effects remain poorly understood.MethodsWe investigated β2GPI’s influence on lipoprotein profiles using β2GPI knockout (KO) and wild-type (WT) mice subjected to normal chow (NC) and high-fat (HF) diets, as well as plasma from β2GPI-deficient patients and aged and sex matched controls. Lipoprotein fractions were analyzed for cholesterol and apolipoprotein content, and protein interactions were assessed by co-immunoprecipitation.ResultsIn animal studies, female β2GPI KO mice—but not males—displayed significantly increased total plasma cholesterol on a HF diet and greater cholesterol content within HDL fractions. Apo E was enriched in HDL fractions from female KO mice under both NC and HF diets, and plasma Apo E was elevated in HF-fed female KOs. In WT females on HF diet, β2GPI was enriched in HDL fractions, and β2GPI co-immunoprecipitated with Apo E. In human studies, the β2GPI-deficient female patient exhibited increased HDL cholesterol, a shift toward larger HDL particles, and enriched Apo E in HDL fractions relative to controls. Co-immunoprecipitation confirmed β2GPI–Apo E interaction in human plasma, with binding requiring Domain V of β2GPI.ConclusionsOur findings identify β2GPI as a sex-specific regulator of HDL metabolism. In females, β2GPI modulates Apo E-containing HDL particles, influencing cholesterol distribution and lipoprotein composition. These results reveal a novel mechanism linking β2GPI to lipid homeostasis, with potential implications for cardiovascular risk in women with autoimmune disease. Targeting β2GPI–Apo E interactions may represent a therapeutic avenue for correcting dysregulated HDL metabolism in female-specific cardiometabolic and autoimmune contexts.

Dietary phytosterols exert hypocholesterolemic effects by inhibiting cholesterol absorption in the small intestine. However, oxidised phytosterols exert harmful effects. In this study, we compared the effects of dietary stigmasterol or oxidised stigmasterol (OS) on cholesterol absorption and metabolism in mice. Institute of Cancer Research (ICR) male mice were fed one of the following diets: a standard American Institute of Nutrition (AIN) diet; the standard diet plus 0·25 % cholesterol; the standard diet plus 0·25 % cholesterol and 0·25 % stigmasterol or the standard diet plus 0·25 % cholesterol and 0·25 % OS. Stigmasterol, but not OS, decreased plasma total cholesterol levels. Unlike stigmasterol, dietary OS increased the cholesterol levels in micellar solutions. Thus, OS could not exert hypocholesterolemic effects as it could not displace cholesterol in micellar solutions. In contrast, dietary OS downregulates the mRNA expression of genes involved in cholesterol synthesis and upregulates the mRNA expression of genes involved in cholesterol catabolism in mice fed cholesterol. In addition, dietary stigmasterol and OS increased the levels of faecal-neutral steroids by downregulating the mRNA expression of Niemann-Pick C1-like 1 protein (NPC1L1) in the small intestine. Dietary stigmasterol may directly regulate the mRNA expression of NPC1L1, whereas dietary OS may reduce the mRNA expression of sterol regulatory element-binding protein 2 and act as a Liver X receptor α agonist, reducing the mRNA expression of NPC1L1. Therefore, OS may affect cholesterol absorption and metabolism through a mechanism different from that of stigmasterol.