Triglycerides Research Articles

Evaluation of thiol/disulphide and oxidant-antioxidant status of dairy cows in periparturient and post-partum period.

Thiol/disulphide homeostasis (TDH) has a critical role in many cellular activities such as antioxidant protection. Alterations of oxidative stress in the transition period play an important role in development of some diseases and disorders in dairy cows. The purpose of this study is to assess the total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), total thiol, native thiol, disulphide and lipid profile in Simmental and Montofon dairy cows (aged 2-3) before and after calving. Blood samples were collected 233-280 days of pregnancy and the 30 days of post-partum. Serum total thiol, native thiol and disulphide levels were determined as well as TAS, TOS and paraoxonase-1 (PON-1) levels were measured using colorimetric assays. Triglycerides (TG), total cholesterol, HDL cholesterol and LDL cholesterol levels were measured with an automatic analyser. Total thiol (p=0.038) and disulphide (p=0.015) levels were higher after calving compare to pregnancy in Montofon. TAS was found lower (p<0.001), and OSI was higher in both breeds (Montofon p=0.012, Simmental p=0.028) after calving than in pregnancy. When compared between pregnancy and after calving levels in the same breed, HDL was found to be higher after calving (p<0.001) and TG was lower after calving (p=0.020) in Montofon. PON (p=0.090), HDL (p<0.001) and cholesterol levels were found higher (p<0.001) and TG level was lower (p<0.001) after calving in Simmental. According to our results, we observed different responses between two breeds before and after calving. There are few studies about TDH in animal research, and this is the first study in the literature that evaluates the TDH along with oxidative stress and lipid profiles in dairy cows in the periparturient and post-partum period.

Lactucin ameliorates FFA-induced steatosis in HepG2 cells by modulating mitochondrial homeostasis through the SIRT1/PGC-1α signaling axis

Nonalcoholic fatty liver disease is a complex disease involving abnormal liver metabolism. Its strong association with metabolic dysfunction has led to a change in nomenclature to metabolism dysfunction-associated fatty liver disease (MAFLD). MAFLD pathogenesis involves abnormal accumulation of hepatic lipids that lead to the production of excess free fatty acids (FFAs), which in turn cause an imbalance in hepatic mitochondrial function. Lactucin, a natural compound extracted from Cichorium glandulosum Boiss. et Huet, regulates liver metabolism and protects the liver. However, the potential mechanisms underlying the lactucin-mediated effects in MAFLD require further investigation. In the present study, HepG2 cells were treated with FFAs to establish an in vitro model of MAFLD. Parameters related to lipid accumulation and mitochondrial function, including triglycerides (TG), oil red O-stained lipid droplets, reactive oxygen species (ROS), mitochondrial membrane potential (JC-1), adenine triphosphate (ATP), and complex III were analysed. Morphology of the mitochondria were evaluated by transmission electron microscopy. Furthermore, key proteins in the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) signalling axis and mitochondrial quality control were analysed. The SIRT1 inhibitor EX-527 was used to verify the key role of the SIRT1 signalling pathway. Western blotting showed that lactucin upregulated the expression of SIRT-1, PGC-1α, Nrf1, Tfam, Mfn2, and Opa1, and promoted mitochondrial biosynthesis and kinetics. The results suggest that lactucin restores mitochondrial dynamic homeostasis by upregulating the SIRT1/PGC-1α signalling axis, thereby reducing FFA-induced lipid accumulation in HepG2 cells.

The association between non-HDL cholesterol and high-grade pancreatic neuroendocrine neoplasms.

High-density lipoprotein cholesterol (HDL-c) plays an important role in tumorigenesis in several endocrine-related cancers. Few studies have shown the effect of non-HDL-c in malignant tumors. The present study aimed to identify the association between non-HDL-c and high-grade pancreatic neuroendocrine neoplasms (PNENs). A total of 197 PNEN patients who underwent surgery were analyzed retrospectively. Clinical and histopathological features, such as patients' age and sex, tumor location and size, tumor grade, the level of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and fasting plasma-glucose levels were obtained. Non-HDL-c was calculated as total cholesterol - HDL-c. The relationships between those features and high-grade PNENs were identified using logistic regression analysis. Among the 197 patients with PNENs, a lower HDL-c level was more common seen in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.05). The non-HDL-c/HDL-c ratio was greater in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.01). Similarly, a greater proportion of patients with a non-HDL-c/HDL-c ratio larger than 5 was found in patients with poorly differentiated PNENs than in those with well-differentiation PNENs (P < 0.01). Multivariate logistic analysis showed that the non-HDL-c/HDL-c ratio was positively associated with poorly differentiated PNENs (odds ratio (OR) = 1.45, 95% conference interval (CI):1.13-1.87). Similarly, the risk of poorly differentiated PNENs increased significantly in patients with a non-HDL-c/HDL-c greater than 5 (OR = 14.13, 95%CI: 2.98-66.89). The risk of high-grade PNENs increased in patients with a high non-HDL-c/HDL-c ratio (OR = 1.27, 95% CI: 1.04-1.55), and the risk also increased markedly when the ratio was greater than 5 (OR = 5.00, 95%CI: 1.28-19.49). A high ratio of non-HDL-c/HDL-c was associated with high-grade PNENs or poorly differentiated PNENs.

Associations of Serum Lipid Traits With Fracture and Osteoporosis: A Prospective Cohort Study From the UK Biobank.

Previous studies reveal inconsistent associations between serum lipid traits and the risks of fractures and osteoporosis in the general population. This prospective cohort study analysed data from 414 302 UK Biobank participants (223 060 women and 191 242 men, aged 37-73 years) with serum lipid measurements: apolipoprotein A (Apo A), apolipoprotein B (Apo B), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and lipoprotein A (Lp(a)). Multivariable Cox proportional hazard models with penalized cubic splines were used to explore potential nonlinear associations of each lipid trait with the risks of fractures and osteoporosis. Subgroup analyses by age, sex, BMI categories and pre-existing cardiovascular disease were conducted. Mediation analyses using the g-formula were performed to quantify to which extent bone mineral density (BMD) may mediate the association between serum lipids and fracture risk. Over a median follow-up period of 13.8 years, 25 918 (6.8%) of the 383 530 participants without prior fracture had incident fracture cases, and 7591 (4.1%) of the 184 919 participants with primary care data and without baseline osteoporosis were diagnosed with osteoporosis. TG had nonlinear associations with fractures and osteoporosis, whereas Apo B, TC and LDL-C had linear associations. There were also nonlinear associations of Apo A and HDL-C with fractures. Individuals in the highest quintiles for Apo A (fracture: HR 1.15 [95% CI 1.10, 1.21]; osteoporosis: HR 1.13 [1.02, 1.25]) and HDL-C (fracture: HR 1.27 [1.20, 1.34]; osteoporosis: HR 1.31 [1.18, 1.46]) were associated with higher risks of fractures and osteoporosis. Conversely, those in the highest quintile for Apo B (fracture: HR 0.85 [0.81, 0.89]; osteoporosis: HR 0.86 [0.79, 0.94]), LDL-C (fracture: HR 0.89 [0.85, 0.93]; osteoporosis: HR 0.91 [0.83, 1.00]) and TG (fracture: HR 0.78 [0.74, 0.82]; osteoporosis: HR 0.75 [0.68, 0.82]) were associated with lower risks. The associations of Apo A (ratio of HR [RHR] 1.05 [1.02, 1.09]) and HDL-C (RHR 1.06 [1.03, 1.09]) with fracture risk were more pronounced in men compared to women. Except for TG and Lp(a), the associations between serum lipids and fractures appear to be partially mediated through BMD (mediation proportions: 5.30% to 40.30%), assuming causality. Our study reveals a complex interplay between different lipid markers and skeletal health, potentially partially mediated through BMD. Routine lipid profile assessments, including HDL-C and Apo A among other lipid traits, may be integrated into the strategies for fracture risk stratification.

Small hepatitis B virus surface antigen (SHBs) induces dyslipidemia by suppressing apolipoprotein-AII expression through ER stress-mediated modulation of HNF4α and C/EBPγ.

Persistent infection with hepatitis B virus (HBV) often leads to disruptions in lipid metabolism. Apolipoprotein AII (apoAII) plays a crucial role in lipid metabolism and is implicated in various metabolic disorders. However, whether HBV could regulate apoAII and contribute to HBV-related dyslipidemia and the underlying mechanism remain unclear. This study revealed significant reductions in apoAII expression in HBV-expressing cell lines, the serum, and liver tissues of HBV-transgenic mice. The impact of HBV on apoAII is related to small hepatitis B virus surface antigen (SHBs). Overexpression of SHBs decreased apoAII levels in SHBs-expressing hepatoma cells, transgenic mice, and the serum of HBV-infected patients, whereas suppression of SHBs increased apoAII expression. Mechanistic investigations demonstrated that SHBs repressed the apoAII promoter activity through a HNF4α- and C/EBPγ-dependent manner; SHBs simultaneously upregulated C/EBPγ and downregulated HNF4α by inhibiting the PI3K/AKT signaling pathway through activating endoplasmic reticulum (ER) stress. Serum lipid profile assessments revealed notable decreases in high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) in SHBs-transgenic mice compared to control mice. However, concurrent overexpression of apoAII in these mice effectively counteracted these reductions in lipid levels. In HBV patients, SHBs levels were negatively correlated with serum levels of HDL-C, LDL-C, TC, and TG, whereas apoAII levels positively correlated with lipid content. This study underscores that SHBs contributes to dyslipidemia by suppressing the PI3K/AKT pathway via inducing ER stress, leading to altered expression of HNF4α and C/EBPγ, and subsequently reducing apoAII expression.IMPORTANCEThe significance of this study lies in its comprehensive examination of how the hepatitis B virus (HBV), specifically through its small hepatitis B virus surface antigen (SHBs), impacts lipid metabolism-a key aspect often disrupted by chronic HBV infection. By elucidating the role of SHBs in regulating apolipoprotein AII (apoAII), a critical player in lipid processes and associated metabolic disorders, this research provides insights into the molecular pathways contributing to HBV-related dyslipidemia. Discovering that SHBs downregulates apoAII through mechanisms involving the repression of the apoAII promoter via HNF4α and C/EBPγ, and the modulation of the PI3K/AKT signaling pathway via endoplasmic reticulum (ER) stress, adds critical knowledge to HBV pathogenesis. The research also shows an inverse correlation between SHBs expression and key lipid markers in HBV-infected individuals, suggesting that apoAII overexpression could counteract the lipid-altering effects of SHBs, offering new avenues for understanding and managing the metabolic implications of HBV infection.

The assessment of myopenia and muscle biopsy in pediatric patients with liver disease awaiting liver transplantation – A cross-sectional analysis

Little is known about the skeletal muscle characteristics (fibre type proportion and size, location of nuclei, presence of fat infiltration) in children with liver disease with radiologically determined myopenia (low muscle mass). During liver transplantation (LTx) surgery, biopsies from the rectus abdominis muscle were collected. Muscle fibre types (I, I/IIA, IIA, IIA/X, IIX) and CSA index (µm/m2) were determined using immunofluorescence staining. Triacylglycerol (TAG) and phospholipid content of muscle was determined using gas chromatography. Myopenia was defined using study-specific cut offs (skeletal muscle index &lt;-2SD) from age-sex matched healthy control scans. Myopenia was prevalent in 41% of children. Children also had a high prevalence of high muscle adiposity (37%). Children with myopenia were older (8.4 vs. 0.7 yrs; p&lt;0.001), had smaller total (median 595 vs. 844 µm/m2; p=0.04) and hybrid IIA/X (612±143 vs. 993±341 µm/m2; p=0.04) muscle fibre size index, lower prevalence of type I fibres (53 vs. 64%; p=0.01) and higher prevalence of type IIA/X hybrid fibres (median 7.5 vs. 0%; p=0.04). Children with myopenia also had a higher prevalence of elevated TAG content (&gt;75 percentile) within the muscle compared to children without myopenia (36% vs 0%; p=0.009). Percent of muscle fibres with centralized nuclei were not different between groups. In conclusion, children with myopenia experience differences in skeletal muscle biological characteristics when compared to children without myopenia at LTx and these findings may have implications for dietary and exercise rehabilitation pre-and post-LTx.

Rationale and design of the SHASTA-3 and SHASTA-4 studies: randomized, double-blind, placebo-controlled, phase 3 studies of plozasiran in patients with severe hypertriglyceridemia

Abstract Severe hypertriglyceridemia (sHTG) confers an increased risk of atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis (AP). sHTG-associated AP is a substantial source of morbidity, mortality, reduced quality of life and financial burden to health care systems. Currently available therapeutic approaches for sHTG are often insufficient to reduce triglyceride (TG) levels and prevent AP. Plozasiran, an investigational siRNA therapeutic, inhibits hepatic production of apolipoprotein C3 (APOC3), a key regulator of lipoprotein lipase-mediated TG metabolism and clearance. In a phase 2 study of sHTG patients [TG ≥500 mg/dL (≥5.65 mmol/L)], plozasiran demonstrated durable reductions in TG levels of up to -80%, 12 weeks after the last dose, and decreased TG below 500 mg/dL (5.65 mmol/L), a threshold of increased risk for AP in most participants. The SHASTA-3 and SHASTA-4 trials will evaluate safety and efficacy of plozasiran, including AP rates, in patients with sHTG. SHASTA-3 and SHASTA-4 are phase 3, randomized, double-blind, placebo-controlled, multi-center trials. Key inclusion criteria are prior sHTG and fasting TG ≥500 mg/dL (≥5.65 mmol/L), at screening. Key exclusion criteria include use of any hepatocyte targeted siRNA treatments that target lipids and/or TGs within 1 year (except inclisiran at least 4 weeks prior to enrollment), siRNA or ASO within 60 days, known FCS diagnosis, and AP within 4 weeks of screening. 700 adults with sHTG will be enrolled in these two trials in several sites across multiple countries. Patients will be randomized 2:1 to receive 4 quarterly subcutaneous injections of plozasiran 25 mg or matching placebo over a 1-year double-blinded period, followed by post-treatment evaluation or entry into the open-label extension study. The randomization will be stratified based on TG levels (≥880 mg/dL vs &amp;lt;880 mg/dL [≥ vs &amp;lt;10 mmol/L]) and prior history of AP, within 5 years of screening. The primary efficacy endpoint of the studies is placebo-adjusted percent change in fasting TG from baseline to month 12 with plozasiran. Secondary endpoints include percent change in fasting TG from baseline to month 10 compared to placebo, percent of patients achieving fasting TGs of &amp;lt;500 mg/dL (&amp;lt;5.65 mmol/L) and TGs of &amp;lt;150 mg/dL (&amp;lt;1.69 mmol/L) at month 10 and 12 compared to placebo, and event rate of adjudicated abdominal clinical events including ER visits and hospitalization for abdominal pain attributed to HTG and events of documented pancreatitis. The effect of plozasiran on other lipids and lipoproteins, inflammatory biomarkers, and liver fat content using magnetic resonance imaging-proton density fat fraction will be assessed. Adjudicated major adverse cardiovascular event rates, safety and tolerability will be assessed. SHASTA-3 and SHASTA-4 are designed to determine whether the quarterly-dosed APOC3 siRNA plozasiran, added to standard of care, safely reduces TG levels and the rate of AP in patients with sHTG.

Effect of triglycerides on cardiovascular risk in patients with a first vs. recurrent acute coronary syndrome

Abstract Background Triglyceride (TG) levels have gained increasing interest in the prevention of cardiovascular disease although there is divergent evidence that might be explained by confounding factors. Methods We performed a multicenter and retrospective study using the ongoing registries of acute coronary syndrome (ACS) patients of 7 hospitals from Spain. TG were measured during the hospitalization, and mortality and major adverse cardiovascular events (MACE) were analyzed through follow-up. Results We included 14,483 patients discharged after an ACS, mean age 67.5 (13.3), 28.1% women, and 30.4% with an ST-elevation ACS; 2,378 (16.4%) patients had a previous ACS and were classified as recurrent ACS. Median triglyceride level was 120.5 (interquartile range [IQRS] 90-197) mg/dL and was slightly higher in patients with recurrent ACS (135 IQR 98-186 vs. 129 IQR 95-175; p&amp;lt;0.01). Patients with first vs. recurrent ACS received ticagrelor or prasugrel more frequently at discharge (14.8% vs. 7.4%; p&amp;lt;0.01), but no other differences in medical treatments were observed. Median follow-up was 1223 (interquartile range 570-2040) days. All-cause mortality was 15.0% (n= 2,166), and 34.71% (n=5,019) of the patients experienced a first MACE during follow-up. Patients with recurrent ACS had higher mortality (32.9% vs. 11.4%; p&amp;lt;0.01) and MACE (46.5% vs. 32.4%; p&amp;lt;0.01) rates. Multivariate analysis, adjusted for age, sex, diabetes, previous heart failure, and medical treatments at discharge showed that TG levels were not associated with higher risk of mortality (p=0.29) but with higher risk of MACE (p=0.04). A significant interaction (p=0.01) was observed for TG and previous ACS for both endpoints and, therefore, analyses were performed separately (Figure 1). As shown in Figure 2, TG were associated with higher risk of death in patients with first ACS (p=0.02) but not in patients with recurrent ACS (p=0.48); in contrast, TG were associated with higher risk of MACE (p=0.024) in patients with a recurrent ACS but not in patients with a first ACS (p=0.25). Conclusions Previous ACS modifies the risk of TG on mortality and MACE in patients discharged after an ACS. TG might be considered a target for treatment in patients after a first or recurrent ACS, although the exact impact on outcomes might be different.

Combination therapy with GalNAc-siRNA drugs targeting both PCSK9 and APOC3 resulted in enhanced lipid lowering in mice

Abstract Introduction Aggressive lowering of both atherogenic low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) could reduce residual atherosclerotic cardiovascular disease (ASCVD) risk. Drugs targeting PCSK9 or APOC3 have shown good lipid-lowering effects in clinic. Here, we have developed GalNAc-conjugated siRNAs, RBD7022 targeting PCSK9 and RBD5044 targeting APOC3, as novel therapeutic agents to lower LDL-C and triglyceride (TG) plasma levels respectively. Each drug shows potent and durable effect in silencing its own target. However, it is unknown whether the combined therapy with siRNA drugs targeting both PCSK9 and APOC3 will generate enhanced effects in lipid lowering. Purpose To investigate the effects of fixed-dose combination of RBD7022 and RBD5044 on LDL-C, TG and total cholesterol (TC). Methods RBD7022 and RBD5044 completely match the human PCSK9 and APOC3 transcripts respectively. RBD7022 has 2 nucleotide mismatches with mouse pcsk9, but still shows silencing activity in mice, while RBD5044 has no activity due to 5 mismatches with mouse apoc3. Therefore, humanized APOC3 transgenic mice were used in this study, which had serious hypertriglyceridemia with relatively high cholesterol and TG levels. They were randomized into 8 groups with treatment of RBD7022 (1 mg/kg or 3 mg/kg), RBD5044 (3 mg/kg or 6 mg/kg), or 3 different dose combinations of RBD7022 and RBD5044, as well as PBS control. All animals were administrated once on Day 1. Plasma was collected to quantify lipid biomarkers. Results RBD7022 showed a robust effect on LDL-C reduction, with inhibition rates of 45% in 3 mg/kg and 43% in 6 mg/kg, indicating 3 mg/kg was a saturated dose for RBD7022 in LDL-C lowering. RBD5044 showed a dose-dependent effect on LDL-C reduction, with inhibition rate of 52% at 1 mg/kg and 59% at 3 mg/kg. Interestingly, significantly enhanced LDL-C reduction was observed in the combination groups, with 67% reduction in LDL-C at RBD5044 1 mg/kg plus RBD7022 3 mg/kg, 73% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 3 mg/kg and 78% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 6 mg/kg, showing dose-dependent effects (Figure 1A). Enhanced TC reduction was also found in combination at RBD5044 3 mg/kg plus RBD7022 6 mg/kg compared with RBD5044 or RBD7022 alone. RBD5044 showed a dose dependent effect on TG reduction with inhibition rates of 56% at 1 mg/kg and 83% at 3 mg/kg. RBD7022 treatment alone did not show significant effect on TG reduction. No added effects of RBD7022 on TG levels was found in the combination with RBD5044, indicating the TG lowering was induced by RBD5044. Conclusions The combination of RBD7022 targeting PCSK9 and RBD5044 targeting APOC3 simultaneously reduce LDL-C and TC levels. The combination of RBD7022 and RBD5044 could be a better therapeutic option to further reduce LDL-C, particularly for mixed hyperlipidemia patients and other high-risk individuals with both high LDL-C and high TG levels.Figure 1

SHR-1918, a monoclonal antibody against angiopoietin-like 3, in healthy subjects: a randomized, double-blind, placebo-controlled, phase 1 study

Abstract Background Low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) are important risk factors for atherosclerotic cardiovascular disease. Angiopoietin-like 3 (ANGPTL3) is involved in the regulation of lipid metabolism and can increase serum TG and LDL-C levels by reducing their clearance. SHR-1918 is an ANGPTL3 monoclonal antibody developed to inhibit ANGPTL3 activity, thereby reducing the level of TG and LDL-C. Purpose This phase 1 single ascending dose study aimed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1918 in healthy subjects. Methods Six dose cohorts were planned, including 100, 300, 450, 750, 900 (optional), and 1200 (optional) mg. For each cohort, 12 healthy subjects were enrolled and randomized (9:3) to receive single subcutaneous SHR-1918 or placebo. Subjects were observed for seven days post-dose and followed up to Day 148 for the 100 mg cohort and Day 190 for the other dose cohorts. The primary endpoints were safety and tolerability. Results A total of 72 subjects were enrolled in the six dose cohorts from 100 to 1200 mg (SHR-1918, n = 54; placebo, n = 18). SHR-1918 was well-tolerated at tested doses. Treatment-emergent adverse events (TEAEs) were reported in 49 (90.7%) subjects in the SHR-1918 group and 17 (94.4%) subjects in the placebo group. The most common TEAEs were upper respiratory tract infection (25.9% with SHR-1918 vs. 27.8% with placebo), protein urine present (22.2% vs. 22.2%), and blood uric acid increased (16.7% vs. 16.7%). All TEAEs were mild or moderate in severity. There were no serious adverse events or TEAEs leading to death. Serum concentration of SHR-1918 generally increased with increasing doses. Maximum serum concentration was reached 8.0 to 10.0 days after injection, and mean t½ was 29.4 to 53.3 days across the dose range. SHR-1918 exposure exhibited in a slightly greater-than-dose-proportional manner from 100 to 1200 mg. Serum LDL-C and TG levels markedly and rapidly decreased in all SHR-1918 dose cohorts and remained under the baseline value up to the end of follow-up period for the higher doses, whereas those in the placebo group were above baseline at most follow-up visits (Figure 1 and 2). In the 750 to 1200 mg cohorts, the largest decline in LDL-C from baseline ranged from -46.5% to -49.1%, and the maximum decrease in TG ranged from -67.4% to -82.8%. On Day 85, there remained to be 36.9% to 39.0% reduction in LDL-C and 59.9% to 79.1% reduction in TG for the higher doses. Anti-drug antibody was not detected in SHR-1918-treated subjects. Conclusions SHR-1918 was well-tolerated and showed promising efficacy in healthy subjects. A phase 2 study has initiated to evaluate SHR-1918 in hyperlipidemic patients (NCT06109831).Serum LDL-C after SHR-1918 injectionSerum TG after SHR-1918 injection

Clinical Deep Data Accumulation System (CLIDAS) reveals a "Lipid paradox" of hypertriglyceridemia in Japanese patients

Abstract Background The association between triglycerides (TG), HDL cholesterol (HDL-C) and the prognosis of cardiovascular disease has not been established. Purpose The aim of this study was to elucidate the relationships between the combination of TG and HDL-C levels and the risk of a major adverse cardiac and cerebral events (MACCE) and to verify the usefulness of TG and HDL-C as a risk stratification factor using the Clinical Deep Data Accumulation System (CLIDAS) database. Methods CLIDAS is a database that accumlates electronic medical records in seven tertiary hospitals in Japan including patient characteristics, medications, laboratory test, physiological test, cardiac catheterization, and PCI treatment. We analyzed 9,690 patients who underwent PCI between April 2014 and March 2020. These patients were stratified into the acute coronary syndrome (ACS) group (N=4,135; 43%) and the chronic coronary syndrome (CCS) group (N=5,555; 57%). Furthermore, patients were divided into four groups based on mean serum TG levels (175 mg/dL) and HDL-C levels (40 mg/dL) as cutoff values: high TG/low HDL-C, low TG/low HDL-C, high TG/high HDL-C, and low TG/high HDL-C, and compared for major adverse cardiac and cerebrovascular events (MACCE). The median follow-up duration was 2.5 years. Results The patients with high TG/low HDL-C showed the highest event rates in myocardial infarction among the ACS group. The hazard ratio for high TG/low HDL-C versus low TG/high HDL-C was 1.76 (95% CI, 1.08 to 2.87, P &amp;lt; 0.05) after adjustment for age, sex, eGFR, and mean LDL-C levels, while we observed no risk stratification by the combination of TG and HDL-C levels in the CCS group (Figure 1). In contrast, the patients with low TG levels showed the paradoxically higher event rates of MACCE in both the ACS and CCS groups, as well as cardiovascular death in the CCS group, compared to those with high TG levels (Figure 2). The hazard ratio for low TG/low HDL-C versus high TG/low HDL-C was 3.21 (95% CI, 1.44 to 7.13, P &amp;lt;0.005), and the hazard ratio for low TG/high HDL-C versus high TG/high HDL-C was 2.23 (95% CI, 1.03 to 4.84, P &amp;lt; 0.05) in the CCS group after adjustment for age, sex, eGFR, and mean LDL-C levels. Conclusion In the CLIDAS database, while high TG and low HDL-C levels stratified the risk of ACS, low TG levels showed worsening prognosis for CV death, suggesting a "Lipid paradox" in the real world.Figure 1Figure 2

Absence of coronary artery disease in high-risk sickle cell anemia patients: a new illustration supporting the protective effect of Bilirubin against atherosclerosis?

Abstract Background Sickle cell anemia (SCA) is associated with both cardiac and systemic vascular disorders, which are the leading cause of morbi-mortality. Although these patients cumulate multiple cardiovascular (CV) risk factors, along with chronic inflammation and endothelial activation, some pre-clinical studies underlined a paradoxical protection against atherosclerosis. Purpose The aim of this study was to evaluate the prevalence of coronary artery disease in a high-risk SCA population. Methods From January 2019 to December 2023, consecutive adult patients with SCA were prospectively included in the DREPACOEUR registry to specifically analyze cardiac structure and function. They all had a comprehensive CV evaluation at steady-state in day-hospital including clinical exam, cardiac imaging, rhythm monitoring along with biology analysis. Only patients that underwent coronary imaging (CT coronary angiogram) were included in this study. Results Ninety patients were included. Mean age was 44±12, 50% were male with a high prevalence of systemic hypertension (57%), obstructive sleep apnea (21%) and 10% smokers. Only one patient had history of diabetes while no dyslipidemia (or lipid lowering therapy) was reported. Heart function was mainly preserved with a mean left ventricular ejection fraction (LVEF) of 58±5%. Expectedly, patients showed low hemoglobin level 8,7±1.4g/dL with high hemolysis markers. Glomerular filtration rate was 109 [62; 122] mL/min/m² with 21% having chronic kidney disease. Plasmatic LDLc level was low (0.7±0.3g/L, with 20% &amp;lt;0.5g/l) while triglycerides (TG) were highly variable (1.1±0.7mg/dL). Strikingly, no patient showed signs of significant coronary artery disease, with 87% presenting a calcium score of 0, 77% had a CAD-RADS of 0 while no patient was higher than 2. Correlation and linear regression analysis were performed to find independent parameters associated with LDLc and TG. Total bilirubin was the only variable that correlated with both LDLc and TG (R= -0.37, p&amp;lt;0.001 and R= -0.33, p=0.001 respectively). Conclusion Despite systemic vasculopathy and chronic inflammation, ageing SCA patients showed no significant coronary artery disease. These data are in line with pre-clinical studies suggesting a lipid-lowering role of bilirubin and its protective effect against atherosclerosis.

Lipids as the link between central obesity and diabetes: perspectives from mediation analysis

BackgroundCentral obesity is a well-recognized risk factor for diabetes, yet the potential role of lipids in the diabetes risk associated with central obesity remains unclear. This study aimed to explore the possible mediating role of 11 lipid parameters [high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), non-high-density lipoprotein cholesterol (Non-HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), remnant cholesterol (RC), and ratios of Non-HDL-C/HDL-C, RC/HDL-C, LDL/HDL-C, TG/HDL-C, TC/HDL-C] in the association of central obesity with diabetes risk.MethodsWe utilized data from 15,453 participants in the NAGALA longitudinal cohort to assess the association of baseline central obesity indicators [waist-height ratio (WHtR), waist circumference (WC)] and the 11 lipid parameters with diabetes risk. Mediation analysis models were constructed to explore the mediating role of lipid parameters in the association of WC/WHtR with diabetes.ResultsConfirmatory associative analysis using multivariable Cox regression showed that, except for Non-HDL-C, TC and LD-C, the remaining eight lipid parameters were significantly associated with WC/WHtR and diabetes risk. Mediation analysis indicated that TG, RC, HDL-C, and lipid ratios such as Non-HDL-C/HDL-C ratio, RC/HDL-C ratio, TG/HDL-C ratio, TC/HDL-C ratio and LDL/HDL-C ratio are potential lipids affecting the diabetes risk related to central obesity. Among these, the RC/HDL-C ratio seemed to contribute the most in the WC/WHtR-related diabetes risk association, with a mediation percentage of about 37%. Additionally, lipid ratio parameters appeared to play a more mediating role in the association of central obesity-related diabetes risk than individual lipids.ConclusionsIn central obesity-related diabetes risk, most lipids, especially lipid ratio parameters, play a significant mediating role. Given these findings, we advocate for increased efforts in multifactorial risk monitoring and joint management of diabetes. The evaluation of lipids, particularly lipid ratio parameters, may be holds substantial value in the prevention and management of diabetes risk under close monitoring of central obesity.

Total sugar intake significantly associated with systolic blood pressure in small sample population

Abstract Background Hypertension contributes to 45% of all deaths from heart disease and up to 51% of deaths from strokes. Dietary factors, such as sodium (Na+) and potassium (K+) can play a role, but recent studies have also highlighted the importance of sugar intake on blood pressure. Very few studies have evaluated the impact of these factors and their ratio on cardiometabolic biomarkers. This study aims to assess the impact of dietary sugar intake, Na+, K+ and NA+/K+ ratio on hypertension and cardiometabolic biomarkers. Methods Fasting venous blood was collected to measure glucose, triacylglycerols (TAG), total cholesterol, HDL-c, ApoA1, ApoB, or hs-CRP, with enzymatic and turbidimetric techniques, and oxidized LDL by ELISA, and IL-6 and TNFa by Luminex system, the latter’s in a subset sample. Blood pressure (SBP, DBP, and HR) was measured at least twice with an automatic recorder. Dietary intake was obtained using semi-quantitative FFQ, comprising 82 items, and reported to the previous year. Data was analysed using R software through descriptive analysis and partial correlations adjusted to the participant’s BMI. A significant level of 0.05 was used. Results 78 participants, aged from 19 to 80 years old (M = 48,5±13,5) were evaluated, with 47% taking hypertensive medication. BMI ranged from 19,7 to 41,1 Kg/m2 (M = 29,2±5,4). The average intake of Na+, K+ and NA+/K+ ratio were 3805±1397 mg, 3980±1300 mg and 1.65±0,38, respectively. Total mean sugar intake (% energy) represents 21,4%. No significant correlation was found between Na+ or K+ with SBP, HR, and the cardiometabolic biomarkers (p &amp;gt; 0.05). A positive correlation was found between % sugar intake and SBP (rs = 0,29, p &amp;lt; 0,05), which remains significant after adjusting for BMI, and a positive correlation, in the borderline of significance, with TAG (rs = 0,23, p = 0,0561). Conclusions N+, K+, and their ratio do not associate with SBP, HR and cardiometabolic biomarkers. However, % of sugar intake is positively associated with SBP. Key messages • Sodium and potassium may not always be associated with changes in blood pressure. • Sugar intake might have an important role in the etiopathology of hypertension.

Effectiveness of Internet + E-Coach chronic disease management on blood glucose, lipid levels, liver function, and quality of life in patients with chronic diabetic retinopathy: a comparative study

ObjectiveThis study aims to explore the effect of Internet + E-Coach chronic disease system intervention on fasting blood glucose (FPG), 2-hour postprandial blood glucose(2hPG), fasting serum insulin (FINS), triglyceride (TG), alanine transaminase (ALT) and quality of life in patients with chronic diabetic retinopathy.Methods208 patients with chronic diabetic retinopathy who were treated in the hospital from March 2021 to March 2023 are chosen and separated into two groups by random number Table 104 patients in the control group received routine continuous intervention, and the research group received Internet + E-Coach chronic disease system intervention. The cognition of disease related knowledge, blood related indicators inflammatory factor levels and improvement of life quality between the two groups before intervention, 6 and 12 months after intervention were compared.ResultsBefore the intervention, the comparison between the two groups in disease related knowledge scores, blood glucose, blood lipid, liver function indicators, inflammatory factor, and low vision quality of life scale (CLVQOL) scores was with P > 0.05. After 6 and 12 months of intervention, the research group had significantly higher scores for basic blood glucose intervention, healthy diet, reasonable exercise, and correct medication use compared to the control group (P < 0.05). FPG, 2hPG, TG and ALT in the research group were lower than those in the control group. FINS were higher in the control group, with P < 0.05. Interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and hypersensitive C-reactive protein (Hs-CRP) in the research group were obviously lower than those in the control group (P < 0.05). The scores of far vision, movement and light perception, adjustment ability, reading and fine work, and daily living ability in the research group were higher than those in the control group, with P < 0.05.ConclusionThe intervention of Internet + E-Coach chronic disease system can improve the knowledge of chronic diabetic retinopathy patients about their own condition, stabilize the levels of blood sugar, blood lipid and liver function indicators, reduce the inflammatory reaction of the body, and improve the quality of life.

Reduction of triglyceride-rich lipoproteins with retatrutide in type 2 diabetes may be explained by concurrent reduction in ANGPTL3/8 levels

Abstract Background/Introduction In the recent phase 2 study (NCT04867785) in patients with type 2 diabetes (T2D), retatrutide, an agonist of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors, reduced triglycerides (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) up to 35.0% and 20.7%, respectively. The angiopoietin-like 3/8 complex (ANGPTL3/8) is the most potent circulating inhibitor of lipoprotein lipase (LPL), and its serum levels have been shown to be directly correlated with TG and low-density lipoprotein cholesterol (LDL-C). Purpose In the aforementioned phase 2 study, we examined the effects of retatrutide on circulating ANGPTL3/8 complex concentrations to help understand the mechanism by which retatrutide reduced TG and non-HDL-C. Methods Patients with T2D were randomly assigned to receive once-weekly injections of placebo, 1.5 mg dulaglutide, or retatrutide doses of 0.5 mg, 4 mg, 8 mg, or 12 mg. Fasting serum samples were collected at baseline, week 2, week 4, week 8, week 12, week 16, and week 24, and ANGPTL3/8 levels were measured at all time points using a sensitive and selective immunoassay. Plasma PCSK9 levels were also measured at baseline and 24 weeks. Data were analyzed using a mixed model for repeated measures with log-transformation. Results Baseline ANGPTL3/8 levels (mean 26.3 ng/mL, IQR 17.4-33.0 ng/mL) were not different among all study groups. Mean percent changes of ANGPTL3/8 from baseline at week 24 were -1.3%, -12.0%, -48.7% and -51.0% in 0.5 mg, 4 mg, 8 mg and 12 mg retatrutide groups, respectively (Figure). Percent changes of ANGPTL3/8 in 8 mg and 12 mg retatrutide groups were significantly different from placebo group (p &amp;lt; 0.0001). Mean percent changes of PCSK9 levels from baseline to 24 weeks were not different from placebo for any treatment arm (+6.2%, -3.9%, -3.8% and -9.6% for retatrutide 0.5 mg, 4 mg, 8 mg and 12 mg groups, respectively, and -1.5% for dulaglutide and -6.5% for placebo). Conclusions In patients with T2D, retatrutide dose-dependently decreased serum concentrations of ANGPTL3/8, the most potent circulating LPL inhibitor. These data suggest that retatrutide may reduce TG-rich lipoproteins by decreasing ANGPTL3/8 levels.

Modifying effect of obesity status on the association between low-density lipoprotein cholesterol with incident hemorrhagic stroke: evidence from a community-based longitudinal cohort study in China

Abstract Background Previous results on the association between lipids and hemorrhagic stroke were controversial. Modifying effect of obesity on the association between low-density lipoprotein cholesterol (LDL-C) and hemorrhagic stroke risk in the Chinese community-based population remains unclear. Objectives We aimed to investigate the association between LDL-C and hemorrhagic stroke risk in the Chinese community-based population. In addition, we aimed to explore the potential modifying effect of obesity status, particularly abdominal obesity, on this relationship. Methods A total of 7899 eligible subjects, without history of stroke and myocardial infarction, and any use of lipid-lowering medication at baseline, were enrolled in this study. Levels of LDL-C, total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) were assessed at baseline. The primary endpoint was the hemorrhagic stroke. Abdominal obesity was defined as waist circumference &amp;gt; 90 cm in men and &amp;gt; 85 cm in women. Results Of all participants, the mean age was 56.13 ± 8.87 years, 2848 (36.1%) were male. During a mean 9.71-year follow-up, 66 hemorrhagic strokes occurred. After multivariable adjustment (Figure 1), compared to participants with LDL-C levels 2.6 – 3.4 mmol/L, those with LDL-C levels &amp;lt; 1.8 mmol/L had 3.32 times the risk (hazard ratio [HR]: 3.32; 95% confidence interval [CI]: 1.24, 8.84) of incident hemorrhagic stroke. Compared with participants with TC levels 3.1 – 5.2 mmol/L, HR (95% CI) was 7.82 (2.36, 25.90) for hemorrhagic stroke in those with TC &amp;lt; 3.1 mmol/L. We observed no significant associations between TG or HDL-C levels and hemorrhagic stroke risk. Interaction effects were found between obesity and LDL-C for incident hemorrhagic stroke. Accordingly, significant associations between low LDL-C level (&amp;lt; 1.8 mmol/L) and the risk of incident hemorrhagic stroke were found only among abdominal obesity participants (HR: 3.76; 95% CI: 1.01, 13.97), or those with body mass index (BMI) &amp;gt; = 24 kg/m2 (HR: 3.74; 95% CI: 1.24, 11.34) (Figure 2). Conclusions LDL-C levels &amp;lt; 1.8mmol/L and TC levels &amp;lt; 3.1mmol/L were associated with increased risk of hemorrhagic stroke. Modifying effect of obesity status on the association between low LDL-C level and hemorrhagic stroke was observed in our study.

Association of Triglycerides, HDL, and Waist Circumference with eGFR in patients in private practice

Background: Chronic kidney disease (CKD) is one of the leading causes of mortality and morbidity all over the world. On the other hand, metabolic syndrome has been reported to be associated with adverse renal outcomes. Among the components of metabolic syndrome, diabetes and hypertension are established causes of renal impairment. However, the association of Triglycerides (TGs), High density lipoprotein (HDL), and Waist Circumference (WC) with renal function independently remains understudied. Objectives: The objective of this study was to determine the association of triglycerides, HDL, waist circumference with estimated glomeruar filtration rate (eGFR). Materials and Methods: This cross-sectional study enrolled 100 subjects attending as outpatient in Ibn Sina Diagnostic Centre, Uttara from July 2023 to December 2023. Renal impairment was measured by estimated glomerular filtration rate (eGFR). The eGFR was calculated using the modified modification of diet in renal disease (MDRD) equation. Statistical analyses were performed by using SPSS 25.0 (Statistical Package for Social Science, Inc., Chicago, IL, USA). Continuous variables were expressed as means±standard deviation, and categorical variables as frequencies and proportions. The relationships between renal function with triglycerides, HDL and WC were assessed by correlation coefficient. A p-value &lt;0.05 was considered significant. Results: Among 100 subjects the overall incidence of renal impairment is 13 (13%). Waist Circumference (WC) and high Triglyceride (TG) have inverse relation with eGFR means significant association in developing renal impairment. Conclusion: This study suggests triglyceride and central obesity progress with renal impairment. Therefore, early monitoring and management of triglycerides and central obesity in CKD patients may help in decreasing the progression of the disease and, hence, mortality in CKD patients. EWMCJ Vol. 12, No. 1&amp;2, January-July 2024: 4-8

Inhibition of Accumulation of Neutral Lipids and Their Hydroperoxide Species in Hepatocytes by Bioactive Allium sativum Extract

Our ongoing research suggests that extracts from plant-based foods inhibit the accumulation of lipid droplets (LDs) and oxidized lipid droplets (oxLDs) in liver cells. These findings suggest their potential use in the alleviation of metabolic dysfunction-associated fatty liver disease (MAFLD) and its most severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH). Allium extracts (ALs: AL1–AL9) were used to assess their ability to reduce lipid droplet accumulation (LDA) and oxidized lipid droplet accumulation (oxLDA) by inhibiting neutral lipid accumulation and oxidation in LD. Among the tested Allium extracts, AL1, AL3, and AL6 demonstrated substantial inhibitory effects on the LDA. Furthermore, AL1 extract showed real-time inhibition of LDA in HepG2 cells in DMEM supplemented with oleic acid (OA) within 12 h of treatment. Our lipidomic approach was used to quantify the accumulation and inhibition of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] species in hepatocytes under OA and linoleic acid loading conditions. These results suggest that Allium-based foods inhibit LD accumulation by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. The metabolomic analysis of AL1—the bioactive LDAI extract—using both LC-MS/MS and 1D-NMR [1H, 13C, and Dept (135 and 90)] approaches revealed that AL1 contains mainly carbohydrates and glucoside metabolites, including iridoid glucosides, as well as minor amino acids, organosulfur compounds, and organic acids such as the antioxidant ascorbic acid (KA2 = S13), and their derivatives, suggesting that AL1 could be a potential resource for the development of functional foods and in drug discovery targeting MAFLD/MASH and other related diseases.

Triple-hormone receptor agonist retatrutide significantly improves lipoprotein and apolipoprotein profiles in participants with obesity or overweight

Abstract Background In a phase 2 study in participants who have obesity or overweight but not type 2 diabetes (T2D) (n=338), retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, reduced body weight, glycated hemoglobin, triglycerides (TG), LDL-C and VLDL-C. Purpose To better understand the effects of RETA on the serum lipid profile we analyzed changes in apolipoprotein levels and distribution and size of lipoprotein particles. Methods Adult participants with obesity (BMI ≥30 kg/m2), or overweight (BMI ≥ 27 kg/m2 and &amp;lt; 30 kg/m2) with a weight-related comorbidity, and without T2D were randomized to receive RETA 1, 4, 8, 12 mg or placebo for 48 weeks. Lipids panel (including calculated non-HDL-C), apolipoproteins (apo) and NMR lipoprotein profiles were measured at baseline, 24 and 48 weeks in fasting plasma samples. Data were analyzed using a mixed model for repeated measures after log transformation. Results RETA dose-dependently reduced non-HDL-C up to 22.2% and 26.9% and apoB up to 19.6% and 24.2% at 24 and 48 weeks, respectively (Figure). At 48 weeks, RETA reduced TG and apoC-III levels up to 40.6% and 38.0%, respectively. RETA greatly reduced the total number of TG-rich lipoprotein particles (TRLP) and all subfractions of TRLP (large, medium and small) at 48 weeks (Table). Since the reduction in large and medium TRLP was greater than the reduction in small TRLP, the average size of TRLP was smaller following treatment with RETA. RETA reduced the number of total and highly atherogenic small LDL particles (LDLP), while total and small HDL particles (HDLP) were only slightly reduced. The average size of HDLP increased following treatment with RETA. At 48 weeks, the NMR-derived lipoprotein insulin resistance score was dose-dependently decreased by 27.4%, 31.7% and 32.5% with 4 mg, 8 mg and 12 mg, respectively, following RETA treatment. Conclusions RETA treatment for 48 weeks dose-dependently reduced levels of non-HDL-C and apoB and the number of total and small LDL particles, suggesting an improvement in atherogenic lipoprotein profile and cardiovascular risk in subjects who have obesity or overweight but not T2D.