Serum biomarkers of phthalate exposure, adipose tissue metabolites and 20-years incidence of elevated LDL levels: An exploratory exposome study in the GraMo cohort.

In addition to the well-recognized transport function of lipoproteins, a large body of evidence has demonstrated that lipoproteins also play an important role in host defense as part of the innate immune system (for review, see Ref. 1). One of the key defensive functions is the ability of HDL and other lipoproteins to bind endotoxin (lipopolysaccharide, LPS) and other bacterial products and neutralize their toxic effects. In this issue of the Journal of Lipid Research, Wang et al. (2) provide insights into the structural requirements for LPS neutralization by apolipoprotein A-I. The helical structure of apolipoprotein A-I is based on eight similar 22 amino acid and two 11 amino acid tandem repeats, but the areas required for HDL formation and function can now be attributed to specific regions based on studies of specific mutations (3). The central region (amino acids 144–186) activates LCAT and contributes to HDL maturation and stability. The N(44–65) and C(220–241) terminal repeats are necessary to initiate lipid binding, form nascent HDL, and remove cholesterol from macrophages. A larger portion of the C-terminal region (190–243) is critical for phospholipid binding and promoting cholesterol efflux. Naturally occurring mutations of cysteines in apolipoprotein A-I, such as A-IMilano and A-IParis, are associated with protection against atherosclerosis even when HDL cholesterol levels are decreased (4). The paper by Wang et al. (2) addresses what regions of apolipoprotein A-I are required for neutralization of LPS by substituting other amino acids for specific cysteine residues. Serine substitution of one cysteine (228) in the C-terminal domain dramatically reduced the ability of HDL to neutralize LPS, while another C-terminal substitution (cysteine 195), proximal to the last 22 residue repeat, had little effect. Midregion substitutions (cysteines 107, 129, and 173) also had little effect. On the other hand, substitution in the first N-terminal repeat (cysteine 52) and especially the next region (cysteine 74) formed HDL that was more effective at neutralizing LPS and protecting from LPS induced lung injury. Thus, Wang et al. (2) have shown that, as with cholesterol and phospholipid metabolism, specific regions of apolipoprotein A-I are essential for LPS neutralization. Furthermore, the regions involved in LPS neutralization are different than those involved in cholesterol and phospholipid metabolism. For example, these authors have previously shown (5) that substitution for cysteine residues 129 and 195 impaired lipid binding, while substitutions at 173 and 195 impaired the ability of HDL to promote cholesterol efflux. In contrast, a substitution at 107 had an increased capacity to promote cholesterol efflux. As noted above, the substitutions at 52 and 74 enhanced the ability of HDL to neutralize LPS, yet these substitutions had no effect on HDL structure or the ability of HDL to remove cholesterol from macrophages. Consequently, the increase in protection from LPS makes the 52 and 74 substitutions “super” apolipoproteins A-Is for host defense, with little downside in adversely affecting reverse cholesterol transport and increasing the risk of atherosclerosis. It remains to be seen whether similar naturally occurring mutations occur in humans and whether such mutations in apolipoprotein A-I will have a beneficial effect during gram-negative infections. Additionally, studies should examine whether similar modifications of apolipoprotein A-I will also enhance the neutralization of other toxic bacterial products, such as lipoteichoic acid. Infections activate Toll-like receptors stimulating the secretion of cytokines, which have profound effects on lipid and lipoprotein metabolism (for review, see Ref. 1). The changes in lipid and lipoprotein metabolism are part of the acute phase response (APR), a pattern best known for increases in serum proteins (6). Positive APR proteins are those whose circulating levels increase during the APR while negative APR proteins decrease. Two positive APR proteins, C-reactive protein and serum amyloid A, bind to lipoproteins and hence can be considered to be apolipoproteins. The increases in serum proteins during the APR are transcriptionally mediated and usually driven by activation of transcription at NF-kB and NF-IL-6 response elements (6). However, many of the changes in lipid and lipoprotein metabolism are part of the negative

Background Psoriasis is a chronic, immune-mediated inflammatory disease primarily affecting the skin and joints, but it also induces systemic inflammation that disrupts metabolic processes. This systemic involvement contributes to a myriad of comorbidities, including diabetes, dyslipidemia, hypertension, obesity, cardiovascular disease, and psoriatic arthritis. Objective This study aimed to examine the relationship between psoriasis and the development of dyslipidemia and, ultimately, cardiovascular diseases. Materials and methods A comparative cross-sectional study was conducted with a total of 164 individuals (82 psoriasis cases and 82 controls) within a study period of two years (June 2022 to June 2024). The severity of psoriasis was calculated using the psoriasis area and severity index (PASI) score. Fasting lipid levels and electrocardiography (ECG) were done for patients who consented. Results Among 82 cases, the mean PASI score was 6.89, with the majority (37, 45.1%) having mild psoriasis. The prevalence of dyslipidemia was significantly higher in psoriasis patients (61, 74.3%) compared to controls (34, 41.4%), with the majority (26, 31.71%) having elevated low-density lipoprotein (LDL) levels. The most commonly observed ECG change among psoriasis patients was rhythm abnormalities (17, 20.7%), followed by conduction block (6, 7.3%) and ischemic changes (5, 6.1%), with ECG changes being more prevalent in cases (33, 40.24%) than controls (25, 30.49%), but with no statistical significance. Conclusion The higher prevalence of dyslipidemia, particularly elevated LDL levels, highlights the need for cardiovascular risk assessment in psoriasis patients. Although ECG changes were observed, their relevance to psoriasis needs to be further studied. Overall, this study emphasizes the importance of comprehensive management strategies addressing both dermatological manifestations and associated systemic conditions to improve patient outcomes in psoriasis.

BackgroundRheumatoid arthritis (RA) is an autoimmune systemic chronic inflammatory disorder, which is characterized by joint stiffness, damage, and destruction of bone. In RA patients, the risk of cardiovascular disease is increased by 2–3 folds as compared to the general population. The major burden of RA is the development of cardiovascular diseases, including congestive heart failure, stroke, and myocardial infarction.ObjectivesAssessment of the association of atherogenic indices with C-reactive protein to evaluate CVD risk was one of the purposes of this study. In addition, the association of atherogenic indices with elevated levels of cardiovascular risk factors (LDL-C and TG) was another aim of this study.MethodsThe preferred study design for this study was a hospital based comparative cross-sectional study method. Data were cleaned, coded, and entered into Epi Data version 4.6 software, and exported to SPSS version 20 for further analysis of atherogenic indices, C-reactive protein, and risk factors. The comparison of atherogenic indices and other variables among the case and control groups was estimated by the independent t-test statistical analysis method. All variables with a p-value less than 0.2 during binary linear regression analysis were selected for multinomial logistic regression analysis. The association of atherogenic indices with C-reactive protein and risk factors was computed using multiple logistic regressions. The data were presented using tables and figures for clarification of the study.ResultsThe levels of atherogenic indices were computed for both RA patients and the control group. The values of atherogenic indices were significantly associated with cardiovascular risk factor (CRP ≥ 2mg/L). Atherogenic index of plasma (AIP) and TC/HDL-C ratio had a statistically significant association with an elevated levels of triglycerides (P<0.01). The TC/HDL-Cratio value of the patient had 2.38 folds more likely to have an elevated low density lipoprotein level. In addition, AIP of RA patients had 57.51 and 23.65 folds more to have elevated low density lipoprotein and triglycerides respectively.ConclusionsThe result of this study showed that TC/HDL-C, LDL/HDL-C ratio values, and atherogenic index of plasma had a statistically significant association with elevated level of low density lipoprotein and triglycerides. In addition to this, they have a statistically significant association with the level of C-reactive protein. There was a highly significant statistical association between atherogenic indices, elevated low density lipoprotein, and triglycerides values. Therefore, the result of this finding confirmed that atherogenic indices have a potential role in the prediction and management of CVD risk in RA patients.

The incidence of cardiovascular diseases (CVD) increases after menopause and may be due to changes in the plasma lipid-lipoprotein levels that occur following menopausal transition. Physiological estrogen withdrawal during menopause plays a major role in abnormal lipid metabolism such as elevated low-density lipoprotein concentration. The aim of this study was to determine the relationship between dyslipidemia and the causative factors of metabolic syndrome in postmenopausal women. In this cross-sectional study, 290 postmenopausal Sudanese women were included. Lipid profiles were measured by spectrophotometer, estrogen hormone determined by ELISA, insulin resistance determined by HOMA-2 calculator and lipid accumulation product was calculated by the following equation (waist circumference in cm X triglyceride concentration in mM). The results revealed that total cholesterol, triglycerides, low-density lipoprotein levels and very low-density lipoprotein levels were significantly higher in the postmenopausal women with metabolic syndrome (MS) in comparison to those without the MS. Elevated total cholesterol levels were seen in 51.7 %, elevated triglycerides were seen in 49.7% and elevated low-density lipoprotein levels were seen in 29.3% whereas reduced high density lipoprotein levels were seen in 16.89% of the postmenopausal women. Total cholesterol, triglycerides and very low-density lipoprotein values showed a significant positive correlation with insulin resistance and lipid accumulation and a significant negative correlation with the estrogen hormone level. In addition, high density lipoproteins showed a significant negative correlation with lipid accumulation levels.

Alterations in Adipose Tissue and Hepatic Lipid Kinetics in Obese Men and Women With Nonalcoholic Fatty Liver Disease

Patients infected with hepatitis C virus (HCV) with elevated low-density lipoprotein (LDL) levels achieve higher sustained virologic response (SVR) rates after peginterferon (PegIFN)/ribavirin treatment versus patients with lower LDL. Our aim was to determine whether SVR rates in patients with low/elevated LDL can be improved by dose intensification. In PROGRESS, genotype 1 patients with baseline HCV RNA ≥ 400,000 IU/mL and body weight ≥ 85 kg were randomized to 48 weeks of 180 µg/wk PegIFN α-2a (40 kDa) plus ribavirin (A: 1200 mg/d; B: 1400/1600 mg/d) or 12 weeks of 360 µg/wk PegIFN α-2a followed by 36 weeks of 180 µg/wk, plus ribavirin (C: 1200 mg/d; D: 1400/1600 mg/d). This retrospective analysis assessed SVR rates among patients with low (<100 mg/dL) or elevated (≥ 100 mg/dL) LDL. Patients with high LDL (n=256) had higher baseline HCV RNA (5.86 × 10(6) IU/mL) versus patients with low LDL (n=262; 4.02 × 10(6) IU/mL; P=0.0003). Multiple logistic regression analysis identified a significant interaction between PegIFN α-2a dose and LDL levels on SVR (P=0.0193). The only treatment-related SVR predictor in the nested multiple logistic regression was PegIFN α-2a dose among patients with elevated LDL (P=0.0074); therefore, data from the standard (A+B) and induction (C+D) dose arms were pooled. Among patients with low LDL, SVR rates were 40% and 35% in the standard and induction-dose groups, respectively; SVR rates in patients with high LDL were 44% and 60% (P=0.014), respectively. Intensified dosing of PegIFN α-2a increases SVR rates in patients with elevated LDL even with the difficult-to-cure characteristics of genotype 1, high baseline viral load, and high body weight.

The causation between lipids and renal cancer remains inconclusive. Our purpose is to explore the causal relationships between the three primary lipid metabolism-related substances, namely triglycerides (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) with the risk of renal cancer using Mendelian randomization (MR) methods. Genetic instruments for lipids were acquired from the UK Biobank. Outcome data were from the FinnGen study (1397 renal cancer cases and 204 070). Single-variable MR (SVMR) and multi-variable MR (MVMR) analyses were conducted with TwoSampleMR package based on R 4.0.3. The random-effect inverse-variance weighted (IVW), MR-Egger, weighted-median method, and weighted mode were the four main computing methods. We found that per 1 SD elevated LDL level was causally associated with renal cancer occurrence based on SVMR (OR, 1.31, 95% CI: 1.05-1.64, P= .016). Similar significant associations were found in other methods. However, the results of SVMR did not support significant associations between TG, and HDL with renal cancer risk in all methods. The association between LDL and renal cancer was still significant in MVMR analysis (OR for IVW method: 1.22 per 1 SD higher trait (SD, 95% CI: 1.11-1.34, P< .001; OR for MR-Egger: 1.22 per 1 SD higher trait, 95% CI: 1.01-1.47, P= .042) when taking TG and HDL into consideration. Our study supported that elevated serum LDL levels is causally associated with an increased risk of renal cancer independent of TG and HDL.

Angelica sinensis and Scutellaria baicalensis synergistically alleviates metabolic dysfunction-associated steatohepatitis via promoting adipose tissue-to-liver tissue communication.

Currently, research on understanding adipose tissue (AT) metabolism has increased significantly. AT is an endocrine organ, that releases proteins, specific metabolites, hormones, micro-RNAs and signaling lipids, all involved in a network of inter-organ communication. Among other effects, AT dysfunction contributes to a proinflammatory and diabetogenic state, from an early stage in the disease development. Overweight and obesity have reached epidemic proportions worldwide, which has been linked to the development and progression of high-comorbidity and diseases, such as insulin resistance, type 2 diabetes mellitus, hypertension, and cardiovascular diseases (CVD). Therefore, therapeutic strategies have been devised to modulate the composition of fat stores, including changes in lifestyle and/or pharmacological treatment for weight management or attenuation of cardiometabolic risk factors. As a result, life expectancy has been increasing. However, the population is being overmedicated and secondary adverse effects due to drug usage can be serious. Commonly prescribed drugs for immunosuppression and psychiatric disorders, such as severe depression and anxiety, are known to alter metabolism, particularly, in AT depots. In this review, we discuss important molecular mechanisms in AT, especially in epicardial AT (EAT), that are highly modulated by these drugs, and put forth EAT as a potential therapeutic target for CVD.

Non-alcoholic steatohepatitis: The role of oxidized low-density lipoproteins

High-density lipoprotein remains elevated despite reductions in total cholesterol in fasting adult male elephant seals (Mirounga angustirostris)

To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.

The development and progression of insulin resistance is driven by genetic and enviromental factors and their interactions. Sucrose belongs to nutrition factors with lipogenic impact, induces de novo lipogenesis, reduces fatty acid oxidation and can deteriorate insulin sensitivity. The aim of study was to investigate transcriptome profile in adipose and muscle tissues under standard or high sucrose diet (HSD) (70 kcal% as sucrose) in two strains of rats - Wistar and a strain of hereditary hypertriglyceridemic rats (HHTg) as a polygenic model of metabolic syndrome and insulin resistance. The transcriptome analysis was evaluated in the context of development and progression of insulin resistance. HSD feeding in 2 weeks increased epididymal adipose tissue (EAT) weight in both strains (P diet&amp;lt;0.05), but not body weight. In addition, HSD feeding resulted in elevated levels of fasting glucose (P diet&amp;lt;0.05), insulin (P diet&amp;lt;0.01) and FFA (P diet&amp;lt;0.05, P strain&amp;lt;0.05), but adiponectin was decreased only in HHTg rats (P&amp;lt;0.01). Insulin sensitivity of EAT was significantly reduced (P diet&amp;lt;0.05, P strain&amp;lt;0.05), but HSD did not change triglycerides or insulin sensitivity in muscle. In skeletal muscle, HSD significantly changed expression (FDR&amp;lt;0.05) of 20 transcripts in HHTg and 21 in Wistar (only 2 common). In EAT, HSD significantly changed expression of 810 transcripts in HHTG and 1823 in Wistar (344 common). The most affected pathways were insulin receptor signaling in HHTg and mitochondrial dysfunction and oxidative phosphorylation in Wistar rats. Major regulator nodes of the mechanistic networks included insulin, SCD and miR-27 for HSD effect in HHTg and LIPE, miR-27 and VEGF in Wistar strain. In conclusion, HSD feeding impaired insulin sensitivity in both rat strains. Transcriptomic alterations in adipose tissue precede muscle changes caused by HSD and show distinct patterns in genetically susceptible HHTg model of metabolic syndrome. Disclosure M. Hüttl: None. I. Marková: None. H. Malinska: None. L. Kazdova: None. O. Seda: None.

Conjugated linoleic acid (CLA) causes insulin resistance and hepatic steatosis in conjunction with depletion of adipokines in some rodent models. Our objective was to determine whether the maintenance of adipokines, mainly leptin and adiponectin, by either removing CLA from diets or using an adiponectin enhancer, rosiglitazone (ROSI), could attenuate CLA-induced insulin resistance. Male C57BL/6 mice were consecutively fed two experimental diets containing 1.5% CLA mixed isomer for 4 weeks followed by a diet without CLA for 4 weeks. CLA significantly depleted adiponectin but not leptin and was accompanied by hepatic steatosis and insulin resistance. These effects were attenuated after switching mice to the diet without CLA along with restoration of adiponectin. To further elucidate the role of adiponectin in CLA-mediated insulin resistance, ROSI was used in a subsequent study in male ob/ob mice fed either control (CON) or CLA diet. ROSI maintained significantly higher adiponectin levels in CON- and CLA-fed mice and prevented the depletion of epididymal adipose tissue and the development of insulin resistance. In conclusion, we show that insulin resistance induced by CLA may be related more to adiponectin depletion than to leptin and that maintaining adiponectin levels alone either by removing CLA or using ROSI can attenuate these effects.

We investigated how capsaicin supplementation impacts lipid and glucose metabolism in visceral white (vWAT) and brown adipose tissue (BAT) and the liver following exposure to bisphenol A (BPA), a known endocrine disruptor linked with metabolic disorders. qRT-PCR-based gene expression analysis, biochemical estimations in the above tissues, and inflammatory cytokine concentration were performed in vWAT and liver. BPA exposure increased adipose tissue mass and altered the expression of key genes and transcription factors related to glucose and lipid metabolism. Capsaicin supplementation upregulated PPARγ, PGC1α, DIO2, UCP-1, ACOX1, P2rx7, TMEM119, and PRDM16 while downregulating C/EBPα in vWAT of BPA exposed mice. In BAT, it upregulated PPARγ, SREBP, DIO2, UCP-1 and TMEM119. In the liver, it increased PPARγ/α, PGC1α, BMP4, GLUT-2, IRS-1, LeptinR, and SIRT-1 expression while reducing ACC and FOXO-1 expression. Expression of Nrf2 was increased whereas Nlrp3, MCP-1, IL-6, and Nf-kB were downregulated in liver tissues of mice that received capsaicin as a co-treatment with BPA. Alteration in malondialdehyde, nitrite and levels of antioxidants such as GSH and SOD was also prevented by capsaicin supplementation in adipose and liver tissues upon BPA exposure. Further capsaicin supplementation also prevented BPA-induced alteration in IL-1β, IL-6, and TNFα levels in the liver and vWAT. Capsaicin supplementation potentially prevented metabolic disruptions triggered by BPA through targeted adjustments in gene expression within tissues. These findings highlight the role of dietary compounds, such as capsaicin in reducing the impacts of environmental toxins on health.