[Research progress of lipid-derived parameters in atherosclerotic cardiovascular disease].

Dyslipidemia stands as an autonomous peril in the realm of atherosclerotic cardiovascular maladies. Prompt identification and timely intervention in the case of dyslipidemia hold promise for substantially curbing the onset and fatality rates associated with coronary heart disease. Traditional lipid surveillance metrics employed in clinical settings, such as low-density lipoprotein cholesterol, exhibit notable limitations. Conversely, lipid-derived parameters emerge as formidable contenders, demonstrating a capacity to amalgamate and quantify disparate risk factors and multifactorial etiologies inherent in a given disease. By encompassing a broader spectrum of information than singular indices, these parameters offer a more profound insight into disease progression by virtue of their grounding in the physiological intricacies of lipid metabolism. Drawing upon extant domestic and international guidelines and research, this discourse delineates and synthesizes four lipid-derived parameters with promising clinical applications: atherogenic index of plasma, non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, apolipoprotein B/A1 ratio, and lipoprotein combine index, and forwards a perspective grounded in current strides in clinical research.

Communication: High-Density Lipoprotein-Specific Phospholipid Efflux in Familial Hypercholesterolemia.

OBJECTIVE: Familial hypercholesterolemia (FH) is characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD). Although the role of LDL-C in FH has been studied, the contribution of high-density lipoproteins (HDL) to CVD in FH remains unknown. This study aimed at highlighting the role of HDL in FH. METHODS: HDL-specific phospholipid efflux (HDL-SPE) assay was developed to predict CVD risk. HDL-SPE was examined in FH patients (n=30) and compared with age- and sex-matched non-FH controls (n=60). RESULTS: FH patients had significantly lower HDL-SPE levels (0.90±0.12) than controls (1.12±0.10; p<0.05), despite similar HDL-cholesterol levels in both groups (FH: 57.9±18.7 mg/dl; controls: 57.1±13.8 mg/dl). These differences remained significant after adjusting for confounders. CONCLUSIONS: These findings suggest there may be dysfunctionality of HDL in FH.

High-Density Lipoprotein Subclasses and Their Role in the Prevention and Treatment of Cardiovascular Disease: A Narrative Review.

The association between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) is controversial. HDL-C is one content type of high-density lipoprotein (HDL). HDL consists of diverse proteins and lipids and can be classified into different subclasses based on size, shape, charge, and density, and can change dynamically in disease states. Therefore, HDL-C levels alone cannot represent HDLs' cardioprotective role. In this review, we summarized the methods for separating HDL subclasses, the studies on the association between HDL subclasses and cardiovascular risk (CVR), and the impact of lipid-modifying medications and nonpharmacological approaches (exercise training, dietary omega fatty acids, and low-density lipoprotein apheresis) on HDL subclasses. As HDL is a natural nanoplatform, recombinant HDLs (rHDLs) have been used as a delivery system in vivo by loading small interfering RNA, drugs, contrast agents, etc. Therefore, we further reviewed the HDL subclasses used in rHDLs and their advantages and disadvantages. This review would provide recommendations and guidance for future studies on HDL subclasses' cardioprotective roles.

HDL regulates the risk of cardiometabolic and inflammatory-related diseases: Focusing on cholesterol efflux capacity.

Dyslipidemia, characterized by higher serum concentrations of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglyceride (TG), and lower serum concentrations of high-density lipoprotein cholesterol (HDL-C), is confirmed as a hallmark of cardiovascular diseases (CVD), posing serious risks to the future health of humans. Aside from the role of HDL-C concentrations, the capacity of cholesterol efflux to HDL is being identified as an enssential messurement for the dyslipidemic morbidity. Through inducing the progression of reverse cholesterol transport (RCT), the HDL-related cholesterol efflux plays a vital role in atherosclerotic plaque formation. In addition, increasing results demonstrated that the relationships between cholesterol efflux and cardiovascular events might be influenced by multiple factors, such as atherosclerosis, diabetes, and, inflammatory diseases. These risk factors could affect the intracellular composition of HDL, which might subsqently influence the cholesterol efflux process induced by HDL particle. In the present comprehensive article, we summarize the latest findings which described the modulatory roles of HDL in cardiometabolic disorders and inflammatory related diseases, focusing on its capacity in mediating cholesterol efflux. Moreover, the potential mechanisms whereby HDL regulate the risk of cardiometabolic disorders or inflammatory related diseases, at least partly, via cholesterol efflux pathway, are also well-listed.

Atypical monocyte dynamics in healthy humans in response to fasting and refeeding are distinguished by fasting HDL and postprandial cortisol.

Monocytes are innate immune cells that are continuously produced in bone marrow which enter and circulate the vasculature. In response to nutrient scarcity, monocytes migrate back to bone marrow, where, upon refeeding, they are rereleased back into the bloodstream to replenish the circulation. In humans, the variability in monocyte behavior in response to fasting and refeeding has not been characterized. To investigate monocyte dynamics in humans, we measured blood monocyte fluctuations in 354 clinically healthy individuals after a 12-h overnight fast and at 3 and 6 h after consuming a mixed macronutrient challenge meal. Using cluster analysis, we identified three distinct monocyte behaviors. Group 1 was characterized by relatively low fasting monocyte counts that markedly increased after consuming the test meal. Group 2 was characterized by relatively high fasting monocyte counts that decreased after meal consumption. Group 3, like Group 1, was characterized by lower fasting monocyte counts but increased to a lesser extent after consuming the meal. Although monocyte fluctuations observed in Groups 1 and 3 align with the current paradigm of monocyte dynamics in response to fasting and refeeding, the atypical dynamic observed in Group 2 does not. Although generally younger in age, Group 2 subjects had lower whole body carbohydrate oxidation rates, lower HDL-cholesterol levels, delayed postprandial declines in salivary cortisol, and reduced postprandial peripheral microvascular endothelial function. These unique characteristics were not explained by group differences in age, sex, or body mass index (BMI). Taken together, these results highlight distinct patterns of monocyte responsiveness to natural fluctuations in dietary fuel availability.NEW & NOTEWORTHY Our study composed of adult volunteers revealed that monocyte dynamics exhibit a high degree of individual variation in response to fasting and refeeding. Although circulating monocytes in most volunteers behaved in ways that align with previous reports, many exhibited atypical dynamics demonstrated by elevated fasting blood monocyte counts that sharply decreased after meal consumption. This group was also distinguished by lower HDL levels, reduced postprandial endothelial function, and a delayed postprandial decline in salivary cortisol.

Bridging the Gap Between the Bench and Bedside: Clinical Applications of High-density Lipoprotein Function.

Decades of research have reshaped our understanding of high-density lipoprotein (HDL) , shifting our focus from cholesterol (C) levels to multifaceted functionalities. Epidemiological studies initially suggested an association between HDL-C levels and cardiovascular disease (CVD) risk; however, such a simple association has not been indicated by recent studies. Notably, genome-wide studies have highlighted discrepancies between HDL-C levels and CVD outcomes, urging a deeper exploration of the role of HDL. The key to this shift lies in elucidating the role of HDL in reverse cholesterol transport (RCT), which is a fundamental anti-atherosclerotic mechanism. Understanding RCT has led to the identification of therapeutic targets and novel interventions for atherosclerosis. However, clinical trials have underscored the limitations of HDL-C as a therapeutic target, prompting the re-evaluation of the role of HDL in disease prevention. Further investigations have revealed the involvement of HDL composition in various diseases other than CVD, including chronic kidney disease, Alzheimer's disease, and autoimmune diseases. The anti-inflammatory, antioxidative, and anti-infectious properties of HDL have emerged as crucial aspects of its protective function, opening new avenues for novel biomarkers and therapeutic targets. Omics technologies have provided insights into the diverse composition of HDL, revealing disease-specific alterations in the HDL proteome and lipidome. In addition, combining cell-based and cell-free assays has facilitated the evaluation of the HDL functionality across diverse populations, offering the potential for personalized medicine. Overall, a comprehensive understanding of HDL multifunctionality leads to promising prospects for future clinical applications and therapeutic developments, extending beyond cardiovascular health.

HDL-cholesterol confers sensitivity of immunotherapy in nasopharyngeal carcinoma via remodeling tumor-associated macrophages towards the M1 phenotype.

BACKGROUND: The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal carcinoma (NPC), and the specific biomarker determining the response to immunotherapy in NPC remains uncertain. METHODS: We assessed the associations between pre-immunotherapy and post-immunotherapy serum lipoproteins and survival in a training cohort (N=160) and corroborated these findings in a validation cohort (N=100). Animal studies were performed to explore the underlying mechanisms. Additionally, the relationship between high-density lipoprotein-cholesterol (HDL-C) levels and M1/M2-like macrophages, as well as activated CD8+T cells in tumor tissues from patients with NPC who received immunotherapy, was investigated. RESULTS: The lipoproteins cholesterol, HDL-C, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein A-1 (ApoA1), and apolipoprotein B, were significantly altered after immunotherapy. Patients with higher baseline HDL-C or ApoA1, or those with increased HDL-C or ApoA1 after immunotherapy had longer progression-free survival, a finding verified in the validation cohort (p<0.05). Multivariate analysis revealed that baseline HDL-C and elevated HDL-C post-immunotherapy were independent predictors of superior PFS (p<0.05). Furthermore, we discovered that L-4F, an ApoA1 mimetic, could inhibit tumor growth in NPC xenografts. This effect was associated with L-4F's ability to polarize M2-like macrophages towards an M1-like phenotype via the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65, thereby alleviating immunosuppression in the tumor microenvironment. Importantly, in patients with NPC with high plasma HDL-C levels, the number of M2-like macrophages was significantly decreased, while M1-like macrophages and activated CD8+T cells were notably increased in those with high HDL-C levels. CONCLUSION: Higher baseline HDL-C levels or an increase in HDL-C post-immunotherapy can enhance immunotherapeutic responses in patients with NPC by reprogramming M2-like macrophages towards the M1 phenotype. This suggests a potential role for prospectively exploring ApoA1 mimetics as adjuvant agents in combination with immunotherapy.

Estrogen Induces LCAT to Maintain Cholesterol Homeostasis and Suppress Hepatocellular Carcinoma Development.

Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified lecithin cholesterol acyltransferase (LCAT) as the most highly estrogen-upregulated gene and a biomarker of favorable prognosis. LCAT upregulation inhibited HCC in vitro and in vivo and mediated estrogen-induced suppression of HCC in an ESR1-dependent manner. LCAT facilitated high-density lipoprotein cholesterol production and uptake via the LDLR and SCARB1 pathways. Consistently, high HDL-C levels corresponded to a favorable prognosis in HCC patients. The enhanced HDL-C absorption induced by LCAT impaired SREBP2 maturation, which ultimately suppressed cholesterol biosynthesis and dampened HCC cell proliferation. HDL-C alone inhibited HCC growth comparably to the cholesterol-lowering drug lovastatin, and SREBF2 overexpression abolished the inhibitory activity of LCAT. Clinical observations and cross-analyses of multiple databases confirmed the correlation of elevated LCAT and HDL-C levels to reduced cholesterol synthesis and improved HCC patient prognosis. Furthermore, LCAT deficiency mimicked whereas LCAT overexpression abrogated the tumor growth-promoting effects of ovariectomy in HCC-bearing female mice. Most importantly, HDL-C and LCAT delayed the development of subcutaneous tumors in nude mice, and HDL-C synergized with lenvatinib to eradicate orthotopic liver tumors. Collectively, this study reveals that estrogen upregulates LCAT to maintain cholesterol homeostasis and to dampen hepatocarcinogenesis. LCAT and HDL-C represent potential prognostic and therapeutic biomarkers for targeting cholesterol homeostasis as a strategy for treating HCC. Significance: Estrogen mediates the sex differences in hepatocellular carcinoma development by reducing cholesterol biosynthesis through activation of an LCAT/HDL-C axis, providing strategies for improving liver cancer prevention, prognosis, and treatment.

Increasing the complexity of lipoprotein characterization for cardiovascular risk in type 2 diabetes.

The burden of cardiovascular disease is particularly high among individuals with diabetes, even when LDL cholesterol is normal or within the therapeutic target. Despite this, cholesterol accumulates in their arteries, in part, due to persistent atherogenic dyslipidaemia characterized by elevated triglycerides, remnant cholesterol, smaller LDL particles and reduced HDL cholesterol. The causal link between dyslipidaemia and atherosclerosis in T2DM is complex, and our contention is that a deeper understanding of lipoprotein composition and functionality, the vehicle that delivers cholesterol to the artery, will provide insight for improving our understanding of the hidden cardiovascular risk of diabetes. This narrative review covers three levels of complexity in lipoprotein characterization: 1-the information provided by routine clinical biochemistry, 2-advanced nuclear magnetic resonance (NMR)-based lipoprotein profiling and 3-the identification of minor components or physical properties of lipoproteins that can help explain arterial accumulation in individuals with normal LDLc levels, which is typically the case in individuals with T2DM. This document highlights the importance of incorporating these three layers of lipoprotein-related information into population-based studies on ASCVD in T2DM. Such an attempt should inevitably run in parallel with biotechnological solutions that allow large-scale determination of these sets of methodologically diverse parameters.

Modulation of lipid profile by secretory phospholipase A2 group IIA: Verification with a transgenic mouse model.

We previously demonstrated a positive relation of secretory phospholipase A2 group IIA (sPLA2-IIA) with circulating high-density lipoprotein cholesterol (HDL-C) in patients with coronary artery disease, and sPLA2-IIA increased cholesterol efflux in THP-1 cells through peroxisome proliferator-activated receptor-γ (PPAR-γ)/liver X receptor α/ATP-binding cassette transporter A1 (ABCA1) signaling pathway. The aim of the present study was to examine the role of sPLA2-IIA over-expression on lipid profile in a transgenic mouse model. Fifteen apoE-/- and C57BL/7 female mice received bone marrow transplantation from transgenic SPLA2-IIA mice, and treated with specific PPAR-γ inhibitor GW9662. High fat diet was given after one week of bone marrow transplantation, and animals were sacrificed after twelve weeks. Immunohistochemical staining showed over-expression of sPLA2-IIA protein in the lung and spleen. The circulating level of HDL-C, but not that of low-density lipoprotein cholesterol (LDL-C), total cholesterol, or total triglyceride, was increased by sPLA2-IIA over-expression, and was subsequently reversed by GW9662 treatment. Over-expression of sPLA2-IIA resulted in augmented expression of cholesterol transporter ABCA1 at mRNA level in the aortas, and at protein level in macrophages, co-localized with macrophage specific antigen CD68. GW9662 exerted potent inhibitory effects on sPLA2-IIA-induced ABCA1 expression. Conclusively, we demonstrated the effects of sPLA2-IIA on circulating HDL-C level and the expression of ABCA1, possibly through regulation of PPAR-γ signaling in transgenic mouse model, that is in concert with the conditions in patients with coronary artery disease.

CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice.

Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae-induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.

The Association of the Cholesterol Efflux Capacity with the Paraoxonase 1 Q192R Genotype and the Paraoxonase Activity.

AIMS: Paraoxonase 1 (PON1) binds to high-density lipoprotein (HDL) and protects against atherosclerosis. However, the relationship between functional PON1 Q192R polymorphism, which is associated with the hydrolysis of paraoxon (POXase activity) and atherosclerotic cardiovascular disease (ASCVD), remains controversial. As the effect of PON1 Q192R polymorphism on the HDL function is unclear, we investigated the relationship between this polymorphism and the cholesterol efflux capacity (CEC), one of the biological functions of HDL, in association with the PON1 activity. METHODS: The relationship between PON1 Q192R polymorphisms and CEC was investigated retrospectively in 150 subjects without ASCVD (50 with the PON1 Q/Q genotype, 50 with the Q/R genotype, and 50 with the R/R genotype) who participated in a health screening program. The POXase and arylesterase (AREase: hydrolysis of aromatic esters) activities were used as measures of the PON1 activity. RESULTS: The AREase activity was positively correlated with CEC independent of the HDL cholesterol levels. When stratified by the PON1 Q192R genotype, the POXase activity was also positively correlated with CEC independent of HDL cholesterol. PON1 Q192R R/R genotype carriers had a lower CEC than Q/Q or Q/R genotype carriers, despite having a higher POXase activity. Moreover, in a multiple regression analysis, the PON1 Q192R genotype was associated with the degree of CEC, independent of the HDL cholesterol and POXase activity. CONCLUSIONS: The PON1 Q192R R allele is associated with reduced CEC in Japanese people without ASCVD. Further studies on the impact of this association on the severity of atherosclerosis and ASCVD development are thus called for.

Genetic and Functional Analyses of Patients with Marked Hypo-High-Density Lipoprotein Cholesterolemia.

AIM: This study aimed to analyze two cases of marked hypo-high-density lipoprotein (HDL) cholesterolemia to identify mutations in ATP-binding cassette transporter A1 (ABCA1) and elucidate the molecular mechanism by which these novel pathological mutations contribute to hypo-HDL cholesterolemia in Tangier disease. METHODS: Wild type and mutant expression plasmids containing a FLAG tag inserted at the C-terminus of the human ABCA1 gene were generated and transfected into HEK293T cells. ABCA1 protein expression and cholesterol efflux were evaluated via Western blotting and efflux assay. The difference in the rate of change in protein expression was evaluated when proteolytic and protein-producing systems were inhibited. RESULTS: In case 1, a 20-year-old woman presented with a chief complaint of gait disturbance. Her HDL-C level was only 6.2 mg/dL. Tangier disease was suspected because of muscle weakness, decreased nerve conduction velocity, and splenomegaly. Whole-exome analysis showed compound heterozygosity for a W484* nonsense mutation and S1343I missense mutation, which confirmed Tangier disease. Cholesterol efflux decreased by a mixture of W484* and S1343I mutations. The S1343I mutation decreased the protein production rate but increased the degradation rate, decreasing the protein levels. This patient also had Krabbe disease. The endogenous ABCA1 protein level of macrophage cell decreased by knocking down its internal galactocerebrosidase. Case 2, a 51-year-old woman who underwent tonsillectomy presented with peripheral neuropathy, corneal opacity, and HDL-C of 3.4 mg/dL. Whole-exome analysis revealed compound heterozygosity for R579* and R1572* nonsense mutations, which confirmed Tangier disease. CONCLUSION: Case 1 is a new ABCA1 mutation with complex pathogenicity, namely, a W484*/S1343I compound heterozygote with marked hypo-HDL cholesterolemia. Analyses of the compound heterozygous mutations indicated that decreases in ABCA1 protein levels and cholesterol efflux activity caused by the novel S1343I mutation combined with loss of W484* protein activity could lead to marked hypo-HDL cholesterolemia. Galactocerebrosidase dysfunction could also be a potential confounding factor for ABCA1 protein function.

Endothelial lipase variant T111I does not alter inhibition by angiopoietin-like proteins.

High levels of HDL-C are correlated with a decreased risk of cardiovascular disease. HDL-C levels are modulated in part by the secreted phospholipase, endothelial lipase (EL), which hydrolyzes the phospholipids of HDL and decreases circulating HDL-C concentrations. A 584C/T polymorphism in LIPG, the gene which encodes EL, was first identified in individuals with increased HDL levels. This polymorphism results in a T111I point mutation the EL protein. The association between this variant, HDL levels, and the risk of coronary artery disease (CAD) in humans has been extensively studied, but the findings have been inconsistent. In this study, we took a biochemical approach, investigating how the T111I variant affected EL activity, structure, and stability. Moreover, we tested whether the T111I variant altered the inhibition of phospholipase activity by angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4), two known EL inhibitors. We found that neither the stability nor enzymatic activity of EL was altered by the T111I variant. Moreover, we found no difference between wild-type and T111I EL in their ability to be inhibited by ANGPTL proteins. These data suggest that any effect this variant may have on HDL-C levels or cardiovascular disease are not mediated through alterations in these functions.

Impaired Cholesterol Efflux Capacity rather than Low HDL-C Reflects Oxidative Stress under Acute Myocardial Infarction.

AIMS: Acute myocardial infarction (AMI) causes irreversible damage to cardiomyocytes due to the discontinuation of oxygen supply and leads to systemic oxidative stress. It has been reported that high-density lipoprotein (HDL) particles have antioxidant capacity, and reduced antioxidant capacity is associated with decreased cholesterol efflux capacity (CEC). The purpose of this study was to clarify the usefulness of CEC measurement in patients with AMI. METHODS: We investigated the association between CEC and oxidative stress status in a case-control study. This study included 193 AMI cases and 445 age- and sex-matched controls. We examined the associations of CEC with HDL-cholesterol (HDL-C) and oxidized human serum albumin (HSA), an index of systemic oxidative stress status, and the effect of aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which has been reported to affect HDL-C level and risk for MI, on these associations. RESULTS: Both bivariable and multivariable analyses showed that CEC was positively correlated with HDL-C levels in both AMI cases and controls, with a weaker correlation in AMI cases than in controls. In AMI cases, oxidized HSA levels were associated with CEC in both bivariable and multivariable analyses, but not with HDL-C. These associations did not differ among the ALDH2 genotypes. CONCLUSIONS: CEC, but not HDL-C level, reflects systemic oxidative stress status in patients with AMI. CEC measurement for patients with AMI may be useful in that it provides information on systemic oxidative stress status as well as atherosclerosis risk.

A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells.

BACKGROUND: Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers. METHODS: CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants. RESULTS: The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides. CONCLUSIONS: This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.

Potential association of genetically predicted lipid and lipid-modifying drugs with rheumatoid arthritis: A Mendelian randomization study.

BACKGROUND: Past studies have demonstrated that patients diagnosed with rheumatoid arthritis (RA) often exhibit abnormal levels of lipids. Furthermore, certain lipid-modifying medications have shown effectiveness in alleviating clinical symptoms associated with RA. However, the current understanding of the causal relationship between lipids, lipid-modifying medications, and the risk of developing RA remains inconclusive. This study employed Mendelian randomization (MR) to investigate the causal connection between lipids, lipid-modifying drugs, and the occurrence of RA. METHODS: We obtained genetic variation for lipid traits and drug targets related to lipid modification from three sources: the Global Lipids Genetics Consortium (GLGC), UK Biobank, and Nightingale Health 2020. The genetic data for RA were acquired from two comprehensive meta-analyses and the R8 of FINNGEN, respectively. These variants were employed in drug-target MR analyses to establish a causal relationship between genetically predicted lipid-modifying drug targets and the risk of RA. For suggestive lipid-modified drug targets, we conducted Summary-data-based Mendelian Randomization (SMR) analyses and using expression quantitative trait loci (eQTL) data in relevant tissues. In addition, we performed co-localization analyses to assess genetic confounders. RESULTS: Our analysis revealed no significant causal relationship between lipid and RA. We observed that the genetically predicted 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) -mediated low density lipoprotein cholesterol (LDL-C) (OR 0.704; 95% CI 0.56, 0.89; P = 3.43×10-3), Apolipoprotein C-III (APOC3) -mediated triglyceride (TG) (OR 0.844; 95% CI 0.77, 0.92; P = 1.50×10-4) and low density lipoprotein receptor (LDLR) -mediated LDL-C (OR 0.835; 95% CI 0.73, 0.95; P = 8.81×10-3) were significantly associated with a lowered risk of RA. while Apolipoprotein B-100 (APOB) -mediated LDL-C (OR 1.212; 95%CI 1.05,1.40; P = 9.66×10-3) was significantly associated with an increased risk of RA. CONCLUSIONS: Our study did not find any supporting evidence to suggest that lipids are a risk factor for RA. However, we observed significant associations between HMGCR, APOC3, LDLR, and APOB with the risk of RA.