VLDL Research Articles

Protective Effects of a Brassica nigra Sprout Hydroalcoholic Extract on Lipid Homeostasis, Hepatotoxicity, and Nephrotoxicity in Cyclophosphamide-Induced Toxicity in Rats

Background: Brassica nigra possesses a significant concentration of bioactive compounds and has been demonstrated to have a variety of pharmacological properties, although its sprout has not been extensively studied. Thus, the protective effects of Brassica nigra sprout hydroalcoholic extract (BNSE) on lipid homeostasis, hepatotoxicity, and nephrotoxicity in cyclophosphamide (CYP)-induced toxicity in rats were examined in this study. Methods: Four experimental rat groups (n = 8 for each group) were examined as follows: NR, normal rats that received normal saline by oral gavage daily; CYP, injected with a single dose of CYP at 250 mg kg−1 intraperitoneally (i.p.) and did not receive any treatment, receiving only normal saline by oral gavage daily; CYP + BNSE250, injected with a single dose of CYP at 250 mg kg−1 i.p. and treated with BNSE at 250 mg kg−1 by oral gavage daily for three weeks; and CYP + BNSE500, injected with a single dose of CYP at 250 mg kg−1 i.p. and treated with BNSE at 500 mg kg−1 by oral gavage daily for three weeks. Results: The results indicated a significant increase (p < 0.05) in triglyceride (TG), cholesterol (CHO), low-density lipoprotein cholesterol (LDL-c), and very low-density lipoprotein cholesterol (VLDL-c) levels in CYP-induced toxicity rats. The administration of BNSE at 250 and 500 mg kg−1 significantly (p < 0.05) attenuated TG, CHO, LDL-c, and VLDL-c at values comparable with the NR group. The most efficient treatment for improving the lipid profile and atherogenicity complication was BNSE at 500 mg kg−1, performing even better than 250 mg kg−1. Administrating BNSE at 250 or 500 mg kg−1 improved the liver’s function in a dose-dependent manner. Comparing the lower dose of 250 mg kg−1 of BNSE with 500 mg kg−1 showed that administrating 250 mg kg−1 attenuated alanine transaminase (ALT) by 28.92%, against 33.36% when 500 mg kg−1 was given. A similar trend was observed in aspartate aminotransferase (AST), where 19.44% was recorded for BNSE at 250 mg kg−1 and 34.93% for BNSE at 500 mg kg−1. Higher efficiency was noticed for BNSE at 250 and 500 mg kg−1 regarding alkaline phosphatase (ALP). An improvement of 38.73% for BNSE at 500 mg kg−1 was shown. The best treatment was BNSE at 500 mg kg−1, as it markedly improved liver function, such as total bilirubin (T.B.), in a dose-dependent manner. The administration of BNSE attenuated the total protein (T.P.), albumin, and globulin levels to be close to or higher than the typical values in NR rats. Conclusions: BNSE might be used for its promising hypolipidemic, hepatoprotective, and nephroprotective potential and to prevent diseases related to oxidative stress. Further research on its application in humans is highly recommended.

Dietary supplementation with 25-hydroxyvitamin D3 regulates productive performance, lipid metabolism and gut microbiota in aged laying ducks

The aim of this study was to investigate the effect of dietary supplementation with 25-hydroxyvitamin D3 (25(OH)D3) on productive performance, lipid metabolism and gut microbiota in aged laying ducks. A total of 432 healthy Longyan ducks at 60-week of age were randomly allotted to 6 groups, each with 6 replicates of 12 ducks. Ducks were given a basal diet (without added 25(OH)D3) or that diet supplemented with 800, 1600, 2400, 3200, or 4000 IU/kg 25(OH)D3 for a total of 16 wk. Dietary supplementation with 25(OH)D3 improved egg production, egg mass and average daily feed intake, and decreased the feed conversion ratio (FCR) of ducks during the whole trial period (linear, quadratic; P < 0.05). Supplementation with 25(OH)D3 decreased very low-density lipoprotein (VLDL) content in yolk (P = 0.008), decreased high-density lipoprotein and low-density lipoprotein (LDL) content in plasma (P = 0.002). Hepatic index, VLDL, LDL, triglyceride and total cholesterol content in liver, nonalcoholic fatty liver activity score of liver and alanine aminotransferase content in plasma were decreased with supplementation of 25(OH)D3 (linear or quadratic; P < 0.05). The decreased hepatic apolipoprotein B 100 and lipoprotein lipase expression, and increased hepatic peroxisome proliferator-activated receptor-α and sterol regulatory element binding protein-1 expression resulted from 25(OH)D3 supplementation (linear, quadratic; P < 0.05). Moreover, 25(OH)D3 supplementation increased the villus/crypt ratio (linear, quadratic; P < 0.05) and expression of zonula occludens protein 1 and nuclear factor-κ-gene binding in duodenum (P < 0.05). The supplementation of 25(OH)D3 reduced the abundance of Wittenberg polluted soil-2 bacteria, Synergistota, Bacteroidales, Colidextribacter, Eggerthellaceae, Oscillospira, Oscillibacter, UCG-009, Barnesiellaceae and Lachnospiraceae_UCG-010 in cecal contents (P < 0.05). Dietary requirements for 25(OH)D3 for ducks (60 to 76 wk), were estimated to be 3377 IU/kg for egg production, 3434 IU/kg for egg mass, and 3256 IU/kg for FCR. In summary, dietary 25(OH)D3 supplementation improved productive performance and influenced liver and plasma lipid homeostasis in aged laying ducks, which may be associated with the reduction of bacteria involved in carbohydrate metabolism in the cecum. Supplementing the basal diet with 3250 to 3450 IU/kg 25(OH)D3 is recommended for aged laying ducks (60 to 76 wk).

Protective Effects of Silymarin Co-Administered with CCl4 on Hepatotoxicity and Its Impact on Liver enzymes and Lipid Profile

This study explained the protective effects of silymarin against liver toxicity induced by carbon tetrachloride (CCl4) in female rats. Silymarin, a natural herbal compound extracted from the Milk thistle (Silybum marianum) plant, possesses well-documented antioxidant, anti-inflammatory, and anti-fibrotic properties. In the conducted experiment, rats that received silymarin alongside CCl4 exhibited significant improvements in liver enzyme (ALT, AST, ALP, and GGT) levels and lipid profiles (Total Cholesterol (TC), Triglycerides (TG), Low-Density Lipoprotein (LDL), High-Density Lipoprotein (HDL), and Very Low-Density Lipoprotein (VLDL) compared to those treated only with CCl4. These findings indicate that silymarin may serve as a potential preventive option for reducing liver damage caused by CCl4. Additional research is needed to comprehensively understand silymarin's impact on lipid metabolism and liver injury.

Methionine and vitamin E supplementation improve production performance, antioxidant potential, and liver health in aged laying hens

Sulfur metabolites of methionine (Met) and vitamin E (VE) have antioxidant potential and can maintain liver health in chickens. This study explored the underlying mechanisms of Met sources, the ratio of total sulfur amino acids to lysine (TSAA: Lys), and VE levels on production performances, antioxidant potential, and hepatic oxidation in aged laying hens. Eight hundred and sixty-four, Hy-Line Brown laying hens (70-week age) were divided into 12 treatment groups, each having 6 repeats and 12 birds/each repeat. The dietary treatments consisted of DL-Met (DL-Met), DL-2-hydroxy-4-(methylthio)-butanoic acid (OH-Met), 3 ratios of TSAA: Lys (0.90, 0.95, and 1.00), and 2 levels of VE (20 and 40 g/ton). Albumen height and Haugh unit significantly increased at a lower level of VE (P < 0.05). Triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) in serum and superoxide dismutase (SOD) and catalase activities (CAT) in the liver significantly reduced at 0.95 TSAA: Lys ratio (P < 0.05). Fatty acid synthase (FAS), lipoprotein lipase (LPL), nuclear factor erythroid 2-related factor 2 (Nrf2), and carnitine palmitoyltransferase-1 alpha (CPT-1α) also upregulated at this TSAA: Lys ratio (P < 0.05). Compared with the DL-Met group, the OH-Met group had lower Dipeptidyl Peptidase 4 (DPP4) and higher TC, LDL, and VLDL concentrations (P < 0.05).The expression of FAS,CPT-1α), glutathione (GSH), glutathione disulfide (GSSG), glutathione synthetase (GSS), and Nrf2 were significantly higher in OH-Met compared with the DL-Met group (P < 0.05). OH-Met at 0.95 and DL-Met at 0.90 TSAA: Lys ratio showed higher CAT and lower aspartate aminotransferase (AST) activities. Moreover, OH-Met at 0.90 and DL-Met at 0.95 of the TSAA: Lys ratio had a significant reduction of malondialdehyde (MDA) (P < 0.05). Overall, these results suggest that OH-Met source with a lower level of VE positively influenced production performance and improved liver health in aged laying hens through improved lipid metabolism and hepatic antioxidant function.

Detection of Some Heavy Metals (Mercury and Lead) Pollutants and their Association with Type 2 Diabetes Mellitus (T2DM) in Baghdad, Iraq

Due to the increased use of products carrying heavy metals caused by human factors in the streets of the city of Baghdad and their direct impact on the air, water quality and soil pollution, heavy metals pollution is one of the important environmental problems. As heavy metals cannot be degraded, they accumulate biologically, and, therefore, can directly threaten higher organisms including humans. The current study focused on detecting heavy metals (mercury and lead) to determine the adverse effects and risk of developing type 2 diabetes mellitus (T2DM) in humans. One hundred total blood samples were collected from healthy people and the patients of both sexes who were suffering from T2DM, with mean age of 31 to 75 years, after 8 to 12 hours of fasting. The first group - G1 the control group consisted of 20 health people (6 males and 14 females). The second group - G2 included 40 patients (20 males and 20 females) who had T2DM and were not exposed to any pollutants. The third group - G3 included 40 males with T2DM and also who were exposed to smoke from local electricity generators, as these samples were collected from workers or living near generators and were exposed to air pollution for a long time. Blood samples were collected from each individual by drawing blood from a vein to evaluate each of the biochemical tests, as well as detecting of some heavy metals such as mercury and lead. The results showed that there was a highly significant increase (p≤0.01) when both fasting blood sugar (FBS) and HbA1c were analysed. As for the results of the analysis of the types of lipid profile, there is no significant difference in cholesterol, while there was a significant increase (p≤0.05) in both low-density lipoprotein (LDL) cholestrol and very low density lipoprotein (VLDL) cholestrol and a highly significant increase (p≤0.01) for both triglyceride and high density lipoporotein cholesterol (HDL) cholestrol. The results of the liver function analysis showed that there was no significant difference in the results of the enzyme serum glutamic oxaloacetic transaminase (SGOT) as well as total bilirubin, while there was a significant increase (p≤0.05) in serum glutamate pyruvate transaminase (SGPT). Significant increase (p≤0.01) was detected in the alkaline phosphatase (ALP) enzyme for each of the studied groups. The results of the detection of the presence of heavy metals using the atomic absorption spectrophotometer showed that there was a significant increase (p≤0.01) in lead, and as for mercury, no significant difference was noticed.

Impaired chaperone-mediated autophagy leads to abnormal SORT1 (sortilin 1) turnover and CES1-dependent triglyceride hydrolysis

ABSTRACT SORT1 (sortilin 1), a member of the the Vps10 (vacuolar protein sorting 10) family, is involved in hepatic lipid metabolism by regulating very low-density lipoprotein (VLDL) secretion and facilitating the lysosomal degradation of CES1 (carboxylesterase 1), crucial for triglyceride (TG) breakdown in the liver. This study explores whether SORT1 is targeted for degradation by chaperone-mediated autophagy (CMA), a selective protein degradation pathway that directs proteins containing KFERQ-like motifs to lysosomes via LAMP2A (lysosomal-associated membrane protein 2A). Silencing LAMP2A or HSPA8/Hsc70 with siRNA increased cytosolic SORT1 protein levels. Leupeptin treatment induced lysosomal accumulation of SORT1, unaffected by siLAMP2A co-treatment, indicating CMA-dependent degradation. Human SORT1 contains five KFERQ-like motifs (658VVTKQ662, 730VREVK734, 733VKDLK737, 734KDLKK738, and 735DLKKK739), crucial for HSPA8 recognition; mutating any single amino acid within these motifs decreased HSPA8 binding. Furthermore, compromised CMA activity resulted in elevated SORT1-mediated degradation of CES1, contributing to increased lipid accumulation in hepatocytes. Consistent with in vitro findings, LAMP2A knockdown in mice exacerbated high-fructose diet-induced fatty liver, marked by increased SORT1 and decreased CES1 levels. Conversely, LAMP2A overexpression promoted SORT1 degradation and CES1D accumulation, counteracting fasting-induced CES1D suppression through CMA activation. Our findings reveal that SORT1 is a substrate of CMA, highlighting its crucial role in directing CES1 to lysosomes. Consequently, disrupting CMA-mediated SORT1 degradation significantly affects CES1-dependent TG hydrolysis, thereby affecting hepatic lipid homeostasis.

Immuno-Informatics Insight into the Relationship Between Cholesterol and Cytokines in Cutaneous Leishmaniasis: From clinics to computation.

The role of serum cholesterol and its interactions with cytokines in human cutaneous leishmaniasis (CL) pathophysiology is unknown. This study aimed to evaluate the correlation among serum total cholesterol (TC), very-low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and cytokines (including interleukin [IL] 10), IL-12 and tumour necrosis factor-alpha [TNF-α]) in CL. The cholesterol-cytokine network was analysed to illuminate the pathogenesis of CL. This case-control study was conducted from December 2022 to March 2023 in hospitals within Baghdad and Wasit provinces, Iraq, and included CL and CL-free subjects ranging between 20-30 years of age. The serum samples were analysed via commercial kits to detect TC, IL-10, IL-12, TNF-α, VLDL-C, LDL-C, HDL-C and TG levels. Computational efforts to dissect cholesterol-protein interaction networks were employed using STITCH. A total of 50 CL and 25 control subjects were included. The TC, HDL-C and LDL-C levels in CL patients were markedly lower (P = 0.0001) than in control subjects, whereas the IL-10, IL-12, TNF-α, VLDL-C and TG levels were higher in CL patients. Serum cholesterol showed no correlation with cytokines; however, a significant correlation (r = 0.57; P = 0.026) was observed between IL-12 and TNF-α. Within the cholesterol-protein network, cholesterol potentially interacted with IL-10, connecting cholesterol to modules with immunological significance, including TRAF1, TRAF2 and TNF receptor superfamily member 1B, as well as IL-10, IL-10RA and IL-12RB1. This study showed the alteration of lipid and lipoprotein in CL and introduced 2 immunological modules in CL, highlighting the importance of the altered cholesterol-cytokine interaction network in CL.

Proteome of Pericytes from Retinal Vasculature of Diabetic Donor Eyes

Retinal pericytes (PCs) are contractile microvascular smooth muscle cells that wrap around the endothelial cells (ECs) maintaining intact retinal vasculature (RV) with a 1:1 ratio. Microvascular complications like Diabetic Retinopathy (DR) due to chronic Diabetes causes apoptotic loss of PCs followed by diminished vessel stability, EC apoptosis, and ischemia, leading to retinal angiogenesis, and eventually severe vision loss. This study aimed to analyze the proteins in PCs isolated from the RV of diabetic human donor eyes and compare them with remaining mixed population (MP) of retinal vascular cells. PCs and MP proteomes were analyzed using semi-quantitative proteomics. Proteins were extracted, quantified, and analyzed in duplicate using LC-MS/MS on a Tandem mass spectrometer. Overall, 42 PC and 27 MP proteins, with 19 shared proteins, were identified. Functional enrichment analysis indicated that PC proteins share common biological processes, such as negative regulation of fibrinolysis and vLDL particle remodeling, nitric oxide transport, phospholipid efflux, positive control over the clearance of apoptotic cells, chondrocyte proliferation, lipoprotein lipase activity, and oxidative stress-induced intrinsic atrophic signaling pathways. In the fold enrichment analysis, the PC proteins were associated with cholesterol metabolism, Complement and coagulant, ECM-receptor interaction, longevity regulating pathway, Peroxisome proliferator-activated receptors (PPAR), focal adhesion and PI3 Akt signaling pathways. Among the PC proteins, vitronectin, gelsolin, hornerin, apolipoprotein A1, C3, H, and complement Factors C3, C4, and C9 were identified as the most highly ranked proteins in diabetes. The identified unique proteins of retinal PC could prove beneficial as a therapeutic target in the management of DR.

Liver knockout of MCU leads to greater dysregulation of lipid metabolism in MAFLD

Metabolic-associated fatty liver disease (MAFLD) is a common chronic condition that poses a significant threat to human health. Mitochondrial dysfunction, particularly involving the mitochondrial Ca2+ uniporter (MCU), plays a key role in its pathogenesis. This study aimed to investigate the impact of the MCU gene on hepatic lipid metabolism in mice fed a high-fat diet. Using MCU knockout and wild-type mice, subjected to either a high-fat or normal diet for 14 weeks, we observed notable Steatosis and liver weight gain in MCU-deficient mice. Liver function markers, serum triglycerides, very low-density lipoprotein (VLDL) levels, and ApoB protein expression were all significantly elevated. Mechanistic studies revealed that MCU deletion led to mitochondrial dysfunction, increased oxidative stress. These findings highlight the critical role of the MCU gene in maintaining hepatic lipid balance and suggest its potential as a therapeutic target for managing nonalcoholic fatty liver disease.

Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis.

Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced trans-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells invitro. Administering high-fat diets (HFDs) enriched in TFAs to Ldlr-/- mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a cis-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of SPTLC2 versus SPTLC3 subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.

Metabolomic profiling identifies signatures and biomarkers linking air pollution to dementia risk: A prospective cohort study

Exposure to air pollution has been associated with increased dementia. However, it remains unknown what specific metabolic mechanisms play a role in this relationship. We included 192,300 dementia-free participants from the UK Biobank cohort study. Annual concentrations of air pollution were assessed based on the residential address. Elastic net regression was performed to identify air pollution-related metabolites, and metabolic score was constructed. Cox regression models and covariate balancing generalized propensity scores (CBGPS) regression models were conducted to explore the longitudinal associations between air pollution/metabolic signatures and dementia risk. The underlying mechanisms between air pollution and dementia driven by metabolic signature or specific metabolites were also investigated. A total of 2592 incident dementia cases were documented. We identified the metabolite profiles in response to air pollution exposure, including 87 metabolites for PM2.5, 65 metabolites for PM10, 76 metabolites for NO2, and 71 metabolites for NOx. The air pollution-related metabolic signatures were associated with increased risk of dementia, with hazard ratios (HR) of 1.17 (95 % CI: 1.12, 1.22), 1.06 (95 % CI: 1.02, 1.11), 1.16 (95 % CI: 1.10, 1.21), and 1.17 (95 % CI: 1.12, 1.22) for PM2.5, PM10, NO2 and NOx, respectively. The associations persisted using causal models. Metabolic signatures mediated the associations between air pollution exposure and dementia risk, with mediation proportions ranging from 6.57 % to 12.71 %. Additionally, we observed that a metabolite known as free cholesterol in medium VLDL (M-VLDL-FC) played a crucial mediating role. Our study provides novel insights into the metabolic mechanisms linking air pollution exposure to dementia risk.

Abstract 4125419: Very-Low-Density Lipoprotein Induces Neuronal Growth with Increased Tyrosine Hydroxylase Expression through Cardiomyocyte-Secreted Exosomes in Metabolic Syndrome

Introduction: Metabolic syndrome (MS) is an important predisposing factor for atrial fibrillation, and is highly related to the autonomic nervous system. Triglyceride-rich very-low-density lipoprotein (VLDL) has specific VLDL receptors (VLDLR), which are abundantly expressed in cardiomyocytes. Hypothesis: VLDL affects neuronal growth through cardiomyocyte-secreted exosomes in metabolic syndrome. Goals/Aims: To determine whether exosomes from VLDL-incubated cardiomyocytes can alter neuronal proliferation. Methods/ Approach: HL-1 cardiomyocytes were incubated with VLDL isolated from human subjects with MS, and exosomes were extracted at the end of the incubation period. VLDLR knockdown HL-1 cells were used to determine the role of VLDLR in exosome secretion. The molecular contents of exosomes were determined by mass spectrometry, which identified neurotropic proteins only detected in the exosomes of MS VLDL-incubated cardiomyocytes. We selected transmembrane protein 14B (TMEM14B) to investigate its effect on neuronal proliferation in P19 cells. Results: Regardless of the knockdown or overexpression of VLDLR in HL-1 cardiomyocytes, exosomes isolated from after VLDL incubation were shown to cause 2.062-fold and 2.084-fold expression of tyrosine hydroxylase (TH) in P19 cells, relative to P19 cells induced by non-VLDL-treated HL-1 cardiomyocyte-secreted exosomes. A similar trend could be seen with HL-1 cardiomyocytes without VLDLR editing, as VLDL-incubated HL-1 cardiomyocytes produced exosomes that could cause 1.926-fold increase in P19 TH expression, relative to treatment by exosomes from HL-1 cardiomyocytes without VLDL-incubation. The P19 cells incubated with TMEM14B demonstrated increased neurite length, with an average of 2.342-fold neurite length when compared with that of control cells. Conclusions: VLDL in MS induced HL-1 cardiomyocytes to secrete exosomes containing neurotrophic molecules and increased dendritic growth of neuronal cells. This effect was VLDLR-independent and was partially caused by TMEM14B in the exosomes.

Serum lipid profile of patients with gallstone disease in rural Western Uttar Pradesh

IntroductionGallstone disease is a common gastrointestinal disorder with varying prevalence across regions. This study explores the demographics and lipid profiles of individuals with cholelithiasis, emphasizing the association between metabolic syndrome and gallstone formation.MethodologyA prospective study was conducted, including 100 outpatients with cholelithiasis. Demographic data, lipid profiles, and comorbidities were recorded, and statistical analysis was performed.ResultsA higher prevalence of gallstones was recorded in the 20–29 age group and among females. Lipid profiles revealed elevated levels of total cholesterol, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and triglycerides in individuals with metabolic syndrome. High-density lipoprotein (HDL) levels were notably lower in those with metabolic syndrome. Age and gender disparities in metabolic syndrome prevalence were observed, with statistical significance noted in gender-based differences. Serum thyroid-stimulating hormone (TSH) levels did not significantly differ between individuals with and without metabolic syndrome.ConclusionThe findings indicated elevated lipid profiles, particularly low HDL, are associated with metabolic syndrome in gallstone patients. Further understanding of these associations can aid in preventive strategies and targeted interventions.

Isotretinoin increases non-insulin-based surrogate markers of insulin resistance in acne vulgaris patients

Background Lipid indices, particularly the triglyceride-glucose index (TyG index) and the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio, are simple, reliable, non-insulin-based surrogate markers of insulin resistance that have recently gained prominence. The aim of this study was to evaluate the effect of isotretinoin treatment on surrogate markers of insulin resistance, in particular the TyG index, in patients with acne vulgaris (AV). Materials and methods This retrospective study reviewed the records of 200 patients who received isotretinoin treatment for acne vulgaris at the Department of Dermatology and Venereology between September 2023 and March 2024. Serum fasting glucose, fasting lipid profile [triglyceride (TG), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)] and other biochemical parameters were recorded. Triglyceride-glucose (TyG) index value was calculated with the formula Ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. Pre-treatment values were compared with values after 5 months of treatment. Results TyG index and TG/HDL, TC/HDL, and LDL/HDL ratios all increased statistically significantly (p < 0.001). In addition, a positive correlation was found between pre- and post-treatment TyG index values and pre- and post-treatment TC/HDL, LDL/HDL and TG/HDL ratio values (p < 0.001). Among lipid measurements, triglycerides, total cholesterol, VLDL-C, LDL-C increased statistically significantly (p < 0.001), while HDL-C decreased statistically significantly (p < 0.05). Conclusion The results of this study suggest that isotretinoin treatment may increase insulin resistance in AV patients by increasing surrogate biomarkers of insulin resistance. We also suggest that the TyG index and other lipid indices can be used in treatment follow-up.

Leukemia inhibitory factor receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr−/− mice

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development.Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr−/− mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice.Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.

ApoE Receptor-2 R952Q Variant in Macrophages Elevates Soluble LRP1 to Potentiate Hyperlipidemia and Accelerate Atherosclerosis in Mice.

apoER2 (apolipoprotein E receptor-2) is a transmembrane receptor in the low-density lipoprotein receptor (LDLR) family with unique tissue expression. A single-nucleotide polymorphism that encodes the R952Q sequence variant has been associated with elevated plasma cholesterol levels and increased myocardial infarction risk in humans. The objective of this study was to delineate the mechanism underlying the association between the apoER2 R952Q variant and increased atherosclerosis risk. An apoER2 R952Q mouse model was generated using a CRISPR/Cas9 strategy, intercrossed with LDLR knockout mice, followed by feeding a Western-type high-fat high-cholesterol diet for 16 weeks. Atherosclerosis was investigated by immunohistology. Plasma lipids and lipid distributions among the various lipoprotein classes were analyzed by colorimetric assay. Tissue-specific effects of the R952Q sequence variant on atherosclerosis were analyzed by bone marrow transplant studies. sLRP1 (soluble low-density lipoprotein receptor-related protein 1) was measured in plasma and conditioned media from bone marrow-derived macrophages by ELISA and GST-RAP (glutathione S-transferase-receptor-associated protein) pull-down, respectively. P38 MAPK (mitogen-activated protein kinase) phosphorylation in VLDL (very-low-density lipoprotein)-treated macrophages was determined by Western blot analysis. Consistent with observations in humans with this sequence variant, the apoER2 R952Q mutation exacerbated diet-induced hypercholesterolemia, via impediment of plasma triglyceride-rich lipoprotein clearance, to accelerate atherosclerosis in Western diet-fed LDLR knockout mice. Reciprocal bone marrow transplant experiments revealed that the apoER2 R952Q mutation in bone marrow-derived cells instead of non-bone marrow-derived cells was responsible for the increase in hypercholesterolemia and atherosclerosis. Additional data showed that the apoER2 R952Q mutation in macrophages promotes VLDL-induced LRP1 (low-density lipoprotein receptor-related protein 1) shedding in a p38 MAPK-dependent manner. The apoER2 R952Q mouse model recapitulates characteristics observed in human disease. The underlying mechanism is that the apoER2 R952Q mutation in macrophages exacerbates VLDL-stimulated sLRP1 production in a p38 MAPK-dependent manner, resulting in its competition with cell surface LRP1 to impede triglyceride-rich lipoprotein clearance, thereby resulting in increased hypercholesterolemia and accelerated atherosclerosis.

Sources of variation in the serum metabolome of female participants of the HUNT2 study.

The aim of this study was to explore the intricate relationship between serum metabolomics and lifestyle factors, shedding light on their impact on health in the context of breast cancer risk. Detailed metabolic profiles of 2283 female participants in the Trøndelag Health Study (HUNT study) were obtained through nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).We show that lifestyle-related variables can explain up to 30% of the variance in individual metabolites. Age and obesity were the primary factors affecting the serum metabolic profile, both associated with increased levels of triglyceride-rich very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), amino acids and glycolysis-related metabolites, and decreased levels of high-density lipoproteins (HDL). Moreover, factors like hormonal changes associated with menstruation and contraceptive use or education level influence the metabolite levels.Participants were clustered into three distinct clusters based on lifestyle-related factors, revealing metabolic similarities between obese and older individuals, despite diverse lifestyle factors, suggesting accelerated metabolic aging with obesity. Our results show that metabolic associations to cancer risk may partly be explained by modifiable lifestyle factors.

Investigation of homocysteine level after bariatric metabolic surgery, effect on vitamin B12 and folate levels

BackgroundObesity is a serious health problem with increasing incidence. worldwide and remains one of the most important causes of preventable deaths. We aimed to examine the relationship between Vitamin B12 and Folic acid, which have an important role for human life, and homocysteine is widely recognized for its association with the development of cardiovascular disease, although its role as an independent risk factor remains a topic of ongoing debate.Materials and methodsWe evaluated 126 patients who underwent bariatric metabolic surgery between September 2019-September 2020. In addition to demographic characteristics of the patients, weight, Vitamin B12, folate, HbA1c, cholesterol, triglyceride, ferritin, serum iron, albumin levels at preoperative, postoperative 1st month, 6th month, 12th month follow-ups were analyzed.ResultsPatients with the desired biochemical parameters at the determined follow-up points were identified and two groups were formed as RYGB(n = 43) and SG(n = 7) patients. When biochemical parameters were analyzed between the groups, homocysteine, HbA1c, HDL Cholesterol, VLDL Cholesterol, Total Cholesterol, Triglycerides, Ferritin, Serum Iron levels showed a statistical difference (p < 0.001). Folate (p = 0.064) and albumin (p = 0.257) did not show a significant difference over time. The change in vitamin B12 (p = 0.409) over time was not significant in the SG group, whereas a significant difference was observed in the RYGB group (p < 0.001). When we established a marginal model to determine the factors affecting the change in homocysteine over time, vitamin B12 and folate values.ConclusionsThe relationship between Vitamin B12, folate and homocysteine is important in order to better understand the complications that develop in bariatric metabolic surgery patients, to prevent possible complications and to better manage the process.

Blood lipid profiles associated with metastatic sites in advanced gastric cancer

BackgroundThis study explored the correlation between peripheral blood lipid levels and clinicopathological parameters in patients with advanced gastric cancer (GC), focusing on changes in lipid levels during disease progression.MethodsPathological features and serum lipid profiles of 179 patients with stage III-IV gastric adenocarcinoma were analyzed. Lipid parameters examined included total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein AI (Apo AI), apolipoprotein B (Apo B), lipoprotein(a) (Lp(a)), among others. The total cholesterol-lymphocyte score (TL score) and BMI were also calculated. The association between lipid parameters and clinicopathological characteristics such as age, gender, family history, and metastasis sites was assessed.ResultsIn GC patients, females had higher TG levels than males. Patients with peritoneal metastasis had significantly lower levels of TC, LDL-C, Apo B, and B/A ratio. Those with lung metastasis exhibited higher LDL-C levels and lower levels of VLDL-C. No significant associations were found between lipid levels and metastasis to distant lymph nodes, liver, or bone. Female patients with ovarian metastasis had significantly lower VLDL-C levels. Multivariate analysis revealed low TC as an independent risk factor for peritoneal metastasis, high LDL-C and low VLDL-C levels for lung metastasis, and younger age and low VLDL-C for ovarian metastasis.ConclusionSpecific blood lipid levels are significantly associated with metastatic sites in advanced gastric cancer. Lipid profiles could serve as potential biomarkers for predicting metastatic sites in GC patients.

Rab2A-mediated Golgi-lipid droplet interactions support very-low-density lipoprotein secretion in hepatocytes.

Lipid droplets (LDs) serve as crucial hubs for lipid trafficking and metabolic regulation through their numerous interactions with various organelles. While the interplay between LDs and the Golgi apparatus has been recognized, their roles and underlying mechanisms remain poorly understood. Here, we reveal the role of Ras-related protein Rab-2A (Rab2A) in mediating LD-Golgi interactions, thereby contributing to very-low-density lipoprotein (VLDL) lipidation and secretion in hepatocytes. Mechanistically, our findings identify a selective interaction between Golgi-localized Rab2A and 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) protein residing on LDs. This complex facilitates dynamic organelle communication between the Golgi apparatus and LDs, thus contributing to lipid transfer from LDs to the Golgi apparatus for VLDL2 lipidation and secretion. Attenuation of Rab2A activity via AMP-activated protein kinase (AMPK) suppresses the Rab2A-HSD17B13 complex formation, impairing LD-Golgi interactions and subsequent VLDL secretion. Furthermore, genetic inhibition of Rab2A and HSD17B13 in the liver reduces the serum triglyceride and cholesterol levels. Collectively, this study provides a new perspective on the interactions between the Golgi apparatus and LDs.