Lifestyle factors, glycemic traits, and lipoprotein traits and risk of liver cancer: a Mendelian randomization analysis.

The current state of knowledge on the relationship between lifestyle factors, glycemic traits, lipoprotein traits with liver cancer risk is still uncertain despite some attempts made by observational studies. This study aims to investigate the causal genetic relationship between factors highly associated with liver cancer incidence by using Mendelian randomization (MR) analysis. Employing MR analysis, this study utilized previously published GWAS datasets to investigate whether lifestyle factors, glycemic traits, and lipoprotein traits would affect the risk of liver cancer. The study utilized three MR methods, including inverse variance-weighted model (IVW), MR Egger, and weighted median. Furthermore, MR-Egger analyses were performed to detect heterogeneity in the MR results. The study also conducted a leave-one-out analysis to assess the potential influence of individual SNPs on the MR analysis results. MR-PRESSO was used to identify and remove SNP outliers associated with liver cancer. MR analyses revealed that 2-h glucose (odds ratio, OR 2.33, 95% confidence interval, CI 1.28-4.21), type 2 diabetes mellitus (T2DM, OR 1.67, 95% CI 1.18-2.37), body mass index (BMI, OR 1.67, 95% CI 1.18-2.37), waist circumference (OR 1.78, 95% CI 1.18-2.37) were associated with increased risk of liver cancer. On the contrary, apolipoproteins B (APOB, OR 0.67, 95% CI 0.47-0.97), and low-density lipoprotein (LDL, OR 0.62, 95% CI 0.42-0.92) were negatively related to liver cancer risk. Additionally, after adjusting for BMI, apolipoproteins A-I (APOA-I, OR 0.56, 95% CI, 0.38-0.81), total cholesterol (TC, OR 0.72, 95% CI, 0.54-0.94), and total triglycerides (TG, OR 0.57, 95% CI, 0.40-0.78) exhibited a significant inverse correlation with the risk of liver cancer. This study supports a causal relationship between 2-h glucose, T2DM, BMI, and waist circumference with the increased risk of liver cancer. Conversely, the study reveals a cause-effect relationship between TC, TG, LDL, APOA-I, and APOB with a decreased risk of liver cancer.

Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice.

BACKGROUND: Dysregulation of cholesterol metabolism is associated with the metastasis of triple-negative breast cancer (TNBC). Apolipoprotein A1 (ApoA1) is widely recognized for its pivotal role in regulating cholesterol efflux and maintaining cellular cholesterol homeostasis. However, further exploration is needed to determine whether it inhibits TNBC metastasis by affecting cholesterol metabolism. Additionally, it is necessary to investigate whether ApoA1-based oncolytic virus therapy can be used to treat TNBC. METHODS: In vitro experiments and mouse breast cancer models were utilized to evaluate the molecular mechanism of ApoA1 in regulating cholesterol efflux and inhibiting breast cancer progression and metastasis. The gene encoding ApoA1 was inserted into the adenovirus genome to construct a recombinant adenovirus (ADV-ApoA1). Subsequently, the efficacy of ADV-ApoA1 in inhibiting the growth and metastasis of TNBC was evaluated in several mouse models, including orthotopic breast cancer, spontaneous breast cancer, and human xenografts. In addition, a comprehensive safety assessment of Syrian hamsters and rhesus monkeys injected with oncolytic adenovirus was conducted. RESULTS: This study found that dysregulation of cholesterol homeostasis is critical for the progression and metastasis of TNBC. In a mouse orthotopic model of TNBC, a high-cholesterol diet promoted lung and liver metastasis, which was associated with keratin 14 (KRT14), a protein responsible for TNBC metastasis. Furthermore, studies have shown that ApoA1, a cholesterol reverse transporter, inhibits TNBC metastasis by regulating the cholesterol/IKBKB/FOXO3a/KRT14 axis. Moreover, ADV-ApoA1 was found to promote cholesterol efflux, inhibit tumor growth, reduce lung metastasis, and prolonged the survival of mice with TNBC. Importantly, high doses of ADV-ApoA1 administered intravenously and subcutaneously were well tolerated in rhesus monkeys and Syrian hamsters. CONCLUSIONS: This study provides a promising oncolytic virus treatment strategy for TNBC based on targeting dysregulated cholesterol metabolism. It also establishes a basis for subsequent clinical trials of ADV-ApoA1 in the treatment of TNBC.

Causal association of blood lipids with all-cause and cause-specific mortality risk: a Mendelian randomization study.

Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR[95% CI]:0.93 [0.89-0.97], P value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 [1.01-1.04], P value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.

Associations of educational attainment with Sepsis mediated by metabolism traits and smoking: a Mendelian randomization study.

Objective: Sepsis constitutes a significant global healthcare burden. Studies suggest a correlation between educational attainment and the likelihood of developing sepsis. Our goal was to utilize Mendelian randomization (MR) in order to examine the causal connection between educational achievement (EA) and sepsis, while measuring the mediating impacts of adjustable variables. Methods: We collected statistical data summarizing educational achievement (EA), mediators, and sepsis from genome-wide association studies (GWAS). Employing a two-sample Mendelian randomization (MR) approach, we calculated the causal impact of education on sepsis. Following this, we performed multivariable MR analyses to assess the mediation proportions of various mediators, including body mass index (BMI), smoking, omega-3 fatty acids, and apolipoprotein A-I(ApoA-I). Results: Genetic prediction of 1-SD (4.2 years) increase in educational attainment (EA) was negatively correlated with sepsis risk (OR = 0.83, 95% CI 0.71 to 0.96). Among the four identified mediators, ranked proportionally, they including BMI (38.8%), smoking (36.5%), ApoA-I (6.3%) and omega-3 (3.7%). These findings remained robust across a variety of sensitivity analyses. Conclusion: The findings of this study provided evidence for the potential preventive impact of EA on sepsis, which may be influenced by factors including and metabolic traits and smoking. Enhancing interventions targeting these factors may contribute to reducing the burden of sepsis.

Overexpression of CuZn superoxide dismutase improves high-density lipoprotein function in swine.

Cardiovascular disease (CVD) has been the leading cause of death worldwide. As a chronic inflammatory disease, atherosclerosis (AS) acts as the initiating factor for CVD and reactive oxygen species (ROS) play a vital role in its development. Superoxide dismutases (SOD) can alleviate the detrimental effects of ROS and serve as the first line of defense through detoxifying the products derived from oxidative stress in vivo. Considering the potential preventive effects of high-density lipoprotein (HDL) on AS and the close relationship between CuZn superoxide dismutase (CuZnSOD) and HDL, the present work investigated whether CuZnSOD overexpression in swine could improve the function of HDL. Seven CuZnSOD transgenic swine, constructed by sperm and magnetic nanoparticles, demonstrated overexpressed CuZnSOD in the liver (P < 0.01) but comparable level to control in plasma (P > 0.05). CuZnSOD overexpression significantly down-regulated the levels of triglyceride (TG), apolipoprotein A-I (apoA-I) (P < 0.05), and high-density lipoprotein cholesterol (HDL-C) (P < 0.01) in plasma. In the presence of CuZnSOD overexpression, HDL3 significantly inhibited levels of IL-6 and TNF-α induced by oxidized low-density lipoprotein (oxLDL) (P < 0.05), indicating enhanced anti-inflammatory activity of HDL. At the same time, HDL-mediated cholesterol efflux did not decrease (P > 0.05). CuZnSOD overexpression improves the anti-inflammatory function of HDL despite decreased levels of HDL-C. In Conclusion, CuZnSOD overexpression improves HDL function in swine.

Functional characterization of missense variants affecting the extracellular domains of ABCA1 using a fluorescence-based assay.

Excess cholesterol originating from nonhepatic tissues is transported within HDL particles to the liver for metabolism and excretion. Cholesterol efflux is initiated by lipid-free or lipid-poor apolipoprotein A1 interacting with the transmembrane protein ABCA1, a key player in cholesterol homeostasis. Defective ABCA1 results in reduced serum levels of HDL cholesterol, deposition of cholesterol in arteries, and an increased risk of early onset CVD. Over 300 genetic variants in ABCA1 have been reported, many of which are associated with reduced HDL cholesterol levels. Only a few of these have been functionally characterized. In this study, we have analyzed 51 previously unclassified missense variants affecting the extracellular domains of ABCA1 using a sensitive, easy, and low-cost fluorescence-based assay. Among these, only 12 variants showed a distinct loss-of-function phenotype, asserting their direct association with severe HDL disorders. These findings emphasize the crucial role of functional characterization of genetic variants in pathogenicity assessment and precision medicine. The functional rescue of ABCA1 loss-of-function variants through proteasomal inhibition or by the use of the chemical chaperone 4-phenylbutyric acid was genotype specific. Genotype-specific responses were also observed for the ability of apolipoprotein A1 to stabilize the different ABCA1 variants. In view of personalized medicine, this could potentially form the basis for novel therapeutic strategies.

RVX-208, an inducer of Apolipoprotein A-I, inhibits the particle production of hepatitis B virus through activation of cGAS-STING pathway.

BACKGROUND: Previously, we have demonstrated that Apolipoprotein A-I (ApoA-I) could inhibit the secretion of Hepatitis B virus (HBV), suggesting that stimulation of ApoA-I may block particle production. In the present study, we evaluated the anti-HBV effect of RVX-208, a small-molecule stimulator of ApoA-I gene expression. METHODS: RVX-208 was used to treat HepG2.2.15 cell, a HepG2 derived cell line stably producing HBV virus. Real-time PCR was performed to examine the HBV DNA levels. Magnetic particles, which were coated with anti-HBS or anti-HBE antibody, were used to examine the HBsAg and HBeAg levels in the supernatant of cultured HepG2.2.15 cells in combination with the enzyme conjugates that were prepared with horseradish peroxidase labelled anti-HBS or anti-HBE antibody in a double antibody sandwich manner. RNA-seq, immunoblots and real-time PCR were used to analyze the functional mechanism of RVX-208. RESULTS: RVX-208 could elevate the ApoA-I protein levels in HepG2.2.15 cells. In the meantime, RVX-208 significantly repressed HBV DNA, HBsAg and HBeAg levels in the supernatants of HepG2.2.15 cells. RNA-seq data revealed that RVX-208 treatment not only affected the cholesterol metabolism, which is closely related to ApoA-I, but also regulated signalling pathways that are associated with antiviral immune response. Moreover, mechanistic studies demonstrated that RVX-208 could activate cGAS-STING pathway and upregulate the transcription of a series of interferons, pro-inflammatory cytokines and chemokines with antiviral potential that are at the downstream of cGAS-STING pathway. CONCLUSION: Our study demonstrated that RVX-208, an inducer of ApoA-I, could suppress HBV particle production through activation of cGAS-STING pathway.

Engineering a New IFN-ApoA-I Fusion Protein with Low Toxicity and Prolonged Action.

Recombinant human interferon alpha-2b (rIFN) is widely used in antiviral and anticancer immunotherapy. However, the high efficiency of interferon therapy is accompanied by a number of side effects; this problem requires the design of a new class of interferon molecules with reduced cytotoxicity. In this work, IFN was modified via genetic engineering methods by merging it with the blood plasma protein apolipoprotein A-I in order to reduce acute toxicity and improve the pharmacokinetics of IFN. The chimeric protein was obtained via biosynthesis in the yeast P. pastoris. The yield of ryIFN-ApoA-I protein when cultivated on a shaker in flasks was 30 mg/L; protein purification was carried out using reverse-phase chromatography to a purity of 95-97%. The chimeric protein demonstrated complete preservation of the biological activity of IFN in the model of vesicular stomatitis virus and SARS-CoV-2. In addition, the chimeric form had reduced cytotoxicity towards Vero cells and increased cell viability under viral load conditions compared with commercial IFN-a2b preparations. Analysis of the pharmacokinetic profile of ryIFN-ApoA-I after a single subcutaneous injection in mice showed a 1.8-fold increased half-life of the chimeric protein compared with ryIFN.

Interactions of variants of human apolipoprotein A-I with biopolymeric model matrices. Effect of collagen and heparin.

BACKGROUND: The extracellular matrix (ECM) is a complex tridimensional scaffold that actively participates in physiological and pathological events. The objective of this study was to test whether structural proteins of the ECM and glycosaminoglycans (GAGs) may favor the retention of human apolipoprotein A-I (apoA-I) variants associated with amyloidosis and atherosclerosis. METHODS: Biopolymeric matrices containing collagen type I (Col, a main macromolecular component of the ECM) with or without heparin (Hep, a model of GAGs) were constructed and characterized, and used to compare the binding of apoA-I having the native sequence (Wt) or Arg173Pro, a natural variant inducing cardiac amyloidosis. Protein binding was observed by fluorescence microscopy and unbound proteins quantified by a colorimetric assay. RESULTS: Both, Wt and Arg173Pro bound to the scaffolds containing Col, but the presence of Hep diminished the binding efficiency. Col-Hep matrices retained Arg173Pro more than the Wt. The retained protein was only partially removed from the matrices with saline solutions, indicating that electrostatic interactions may occur but are not the main driving force. Using in addition thermodynamic molecular simulations and size exclusion chromatography approaches, we suggest that the binding of apoA-I variants to the biopolymeric matrices is driven by many low affinity interactions. CONCLUSIONS: Under this scenario Col-Hep scaffolds contribute to the binding of Arg173Pro, as a cooperative platform which could modify the native protein conformation affecting protein folding. GENERAL SIGNIFICANCE: We show that the composition of the ECM is key to the protein retention, and well characterized biosynthetic matrices offer an invaluable in vitro model to mimic the hallmark of pathologies with interstitial infiltration such as cardiac amyloidosis.

Genetic and clinical factors underlying a self-reported family history of heart disease.

AIMS: To estimate how much information conveyed by self-reported family history of heart disease (FHHD) is already explained by clinical and genetic risk factors. METHODS AND RESULTS: Cross-sectional analysis of UK Biobank participants without pre-existing coronary artery disease using a multivariable model with self-reported FHHD as the outcome. Clinical (diabetes, hypertension, smoking, apolipoprotein B-to-apolipoprotein AI ratio, waist-to-hip ratio, high sensitivity C-reactive protein, lipoprotein(a), triglycerides) and genetic risk factors (polygenic risk score for coronary artery disease [PRSCAD], heterozygous familial hypercholesterolemia [HeFH]) were exposures. Models were adjusted for age, sex, and cholesterol-lowering medication use. Multiple logistic regression models were fitted to associate FHHD with risk factors, with continuous variables treated as quintiles. Population attributable risks (PAR) were subsequently calculated from the resultant odds ratios. Among 166 714 individuals, 72 052 (43.2%) participants reported an FHHD. In a multivariable model, genetic risk factors PRSCAD (OR 1.30, CI 1.27-1.33) and HeFH (OR 1.31, 1.11-1.54) were most strongly associated with FHHD. Clinical risk factors followed: hypertension (OR 1.18, CI 1.15-1.21), lipoprotein(a) (OR 1.17, CI 1.14-1.20), apolipoprotein B-to-apolipoprotein AI ratio (OR 1.13, 95% CI 1.10-1.16), and triglycerides (OR 1.07, CI 1.04-1.10). For the PAR analyses: 21.9% (CI 18.19-25.63) of the risk of reporting an FHHD is attributed to clinical factors, 22.2% (CI% 20.44-23.88) is attributed to genetic factors, and 36.0% (CI 33.31-38.68) is attributed to genetic and clinical factors combined. CONCLUSIONS: A combined model of clinical and genetic risk factors explains only 36% of the likelihood of FHHD, implying additional value in the family history.

With advances in genetics, it is tempting to assume that the 'family history' of a patient is an imperfect proxy for information we can already glean from genetics and laboratory tests. However, this study shows that much of the information contained in the self-reported family history of heart disease is not captured by currently available genetic and clinical biomarkers and highlights an important knowledge gap. Clinically used biomarkers explained only 21.9% of the likelihood of a patient reporting a family history of heart disease, while genetics explained 22.2%, and a combined model explained 36% of this likelihoodThe majority of the risk of reporting a family history went unexplained, implying that family history still has major relevance in clinical practice.

Echocardiographic findings in subjects with an amyloidogenic apolipoprotein A1 pathogenic variant.

BACKGROUND: Very small case series of patients with apolipoprotein A1 (ApoA1) amyloidosis are available. METHODS: We described the clinical and echocardiographic characteristics of individuals with the pathogenic APOA1 variant Leu75Pro (p. Leu99Pro), referred for cardiac screening. RESULTS: We enrolled 189 subjects, 54% men, median age 55 years (interquartile range 42-67), 39% with concomitant renal disease and 31% with liver disease. Median left ventricular ejection fraction was 60% (55-66). Overall, these subjects did not show overt diastolic dysfunction nor left ventricular (LV) hypertrophy. Age correlated with interventricular septal (IVS) thickness (r = 0.484), LV mass index (r = 0.459), E/e' (r = 0.501), and right ventricular free wall thickness (r = 0.594) (all p < 0.001). Some individuals displayed red flags for cardiac amyloidosis (CA), and 14% met non-invasive criteria for CA. Twenty-nine subjects died over 5.8 years (4.1-8.0), with 10 deaths for cardiovascular causes. Individuals meeting echocardiographic criteria for CA had a much higher risk of all-cause death (p = 0.009), cardiovascular death (p = 0.001), cardiovascular death or heart failure (HF) hospitalisation (p < 0.001). Subjects with both renal and liver involvement had a more prominent cardiac involvement, and shortest survival. CONCLUSIONS: Subjects with the APOA1 Leu75Pro variant displayed minor echocardiographic signs of cardiac involvement, but 14% met echocardiographic criteria for CA. Subjects with suspected CA had a worse outcome.

Delineating the impact of pathogenic mutations on the conformational dynamics of HDL's vital protein ApoA1: a combined computational and molecular dynamic simulation approach.

Apolipoprotein A1 (ApoA1), is the important component of high-density lipoproteins (HDL), that has key role in HDL biogenesis, cholesterol trafficking, and reverse cholesterol transport (RCT). Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in ApoA1 have been linked to cardiovascular diseases and amyloidosis as they alter the protein's native structure and function. Therefore in this study, we attempted to understand the molecular pathogenicity profile of nsSNPs of ApoA1 using various computational approaches. We used state-of-the-art computational methods to thoroughly investigate the 295 ApoA1 nsSNPs at sequence and structural levels. Seven nsSNPs (L13R, L84R, L84P, L99P, R173P, L187P, and L238P) out of 295 were classified as the most deleterious and destabilizing. In order to estimate the effect of such destabilizing mutations on the protein conformation, all-atom molecular dynamics simulations (MDS) of ApoA1 wild-type (WT), L99P and R173P for 100 ns, was carried out using GROMACS 5.0.1 package. The MD simulation investigation revealed significant structural alterations in L99P and R173P. In addition, they had changed principal component analysis and electrostatic surface potential, decreased structural compactness, and intramolecular hydrogen bonds, which supported the rationale underpinning ApoA1 dysfunction with such mutations. This work sheds light on ApoA1 dysfunction due to single amino acid alterations, and offers new insight into the molecular basis of ApoA1-related diseases progression.Communicated by Ramaswamy H. Sarma.

Apolipoprotein A1 Protects Against Necrotic Core Development in Atherosclerotic Plaques: PDZK1-Dependent High-Density Lipoprotein Suppression of Necroptosis in Macrophages.

BACKGROUND: Atherosclerosis is a chronic disease affecting artery wall and a major contributor to cardiovascular diseases. Large necrotic cores increase risk of plaque rupture leading to thrombus formation. Necrotic cores are rich in debris from dead macrophages. Programmed necrosis (necroptosis) contributes to necrotic core formation. HDL (high-density lipoprotein) exerts direct atheroprotective effects on different cells within atherosclerotic plaques. Some of these depend on the SR-B1 (scavenger receptor class B type I) and the adapter protein PDZK1 (postsynaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1). However, a role for HDL in protecting against necroptosis and necrotic core formation in atherosclerosis is not completely understood. METHODS: Low-density lipoprotein receptor-deficient mice engineered to express different amounts of ApoA1 (apolipoprotein A1), or to lack PDZK1 were fed a high fat diet for 10 weeks. Atherosclerotic plaque areas, necrotic cores, and key necroptosis mediators, RIPK3 (receptor interacting protein kinase 3), and MLKL (mixed lineage kinase domain-like protein) were characterized. Cultured macrophages were treated with HDL to determine its effects, as well as the roles of SR-B1, PDZK1, and the PI3K (phosphoinositide 3-kinase) signaling pathway on necroptotic cell death. RESULTS: Genetic overexpression reduced, and ApoA1 knockout increased necrotic core formation and RIPK3 and MLKL within atherosclerotic plaques. Macrophages were protected against necroptosis by HDL and this protection required SR-B1, PDZK1, and PI3K/Akt pathway. PDZK1 knockout increased atherosclerosis in LDLRKO mice, increasing necrotic cores and phospho-MLKL; both of which were reversed by restoring PDZK1 in BM-derived cells. CONCLUSIONS: Our findings demonstrate that HDL in vitro and ApoA1, in vivo, protect against necroptosis in macrophages and necrotic core formation in atherosclerosis, suggesting a pathway that could be a target for the treatment of atherosclerosis.

Apolipoprotein A1 Inhibits Adipogenesis Progression of Human Adipose-Derived Mesenchymal Stem Cells.

BACKGROUND: According to the reports, the most vital characteristic of obesity is an aberrant accumulation of triglycerides (TG) in the adipocyte. On the other hand, circulating concentrations of apolipoprotein A1 (apoA1) have been demonstrated to be strongly correlated with the prevalence and the pathological development of obesity. Nevertheless, the underlying mechanisms whereby apoA1 modulates the pathogenesis of obesity is still not fully elucidated. METHODS: Adipose-derived mesenchymal stem cells (AMSCs, isolated from the hospitalized patients were combined with 15 µg/ml recombined human apoA1 protein. The effects of apoA1 on modulating the intracellular levels of TG and the expression contents of adipogenic related cytokines were also analyzed. Furthermore, whether apoA1 modulated the adipogenesis progression via sortilin was also explored in the current research. RESULTS: During the adipogenesis progression, apoA1 could significantly lower the quantity of intracellular lipid droplets (LDs). Meanwhile, apoA1 could decrease the intracellular levels of TG and down-regulate the expression contents of several vital adipogenic related cytokines, such as CCAAT enhancer-binding proteins α/ß (C/EBPα/ß), fatty acid synthetase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, the inhibitory effect of apoA1 was further verified to be induced through upregulating the SORT1 gene expression which subsequently increased sortilin protein. Consistent with these findings, silencing the SORT1 gene expression could induce the loss-of-function (LOF) of apoA1 in modulating the adipogenesis progression of AMSCs. CONCLUSION: In conclusion, apoA1 could suppress the adipogenesis progression of human AMSCs through, at least partly, up-regulating the SORT1 gene expression which subsequently increases the sortilin protein content. Thereby, the present research sheds light on a novel pathogenic mechanism by which apoA1 regulates adipogenesis progression and proposes that apoA1 embraces the function to treat obesity in clinical practice.

Elevated expression of ISY1, APOA-1, SYNE1, MTG1, and MMP10 at HCC initiation: HCC specific protein network involving interactions of key regulators of lipid metabolism, EGFR signaling, MAPK, and splicing pathways.

Identification of molecular regulators of hepatocellular carcinoma (HCC) initiation and progression is not well understood. We chemically induced HCC in male Wistar rats by administration of diethyl nitrosamine (DEN) and 2-acetylaminofluorene (2-AFF). Using 2D-electrophoresis and MALDI-TOF-MS/MS analyses, we characterized differentially expressed proteins in liver tissues at early stage of HCC progression. Using RT-PCR analysis, we quantified the mRNA expression of the characterized proteins and validated the transcript expression with tumor tissues of clinically confirmed HCC patients. Using bioinformatic tools, we analyzed a network among the introduced proteins that identified their interacting partners and analyzed the molecular mechanisms associated with signaling pathways during HCC progression. We characterized a protein, namely, pre-mRNA splicing factor 1 homolog (ISY1), which is upregulated at both transcriptome and proteome levels at HCC initiation, progression, and tumor stages. We analyzed the interacting partners of ISY1, namely, APOA-1, SYNE1, MMP10, and MTG1. Real-time PCR analysis confirmed elevated expression of APOA-1 mRNA at HCC initiation, progression, and tumor stages in animals undergoing tumorigenesis. The mRNA expression of the interacting partners was validated with tumor tissues of clinically confirmed liver cancer patients; the analysis revealed significant elevation in expression of transcripts. The transcriptome and proteome analyses complement each other and dysregulation in mRNA and protein expression of these regulators may play critical role in HCC initiation and progression.

Assessment of causal association between differentiated thyroid cancer and disordered serum lipid profile: a Mendelian randomization study.

Background: Research has shown that the disordered serum lipid profile may be associated with the risk of differentiated thyroid cancer (DTC). Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causality of circulating lipoprotein lipids on DTC. Methods: Mendelian randomization (MR) analysis was conducted to evaluate the relationship between the circulating lipoprotein lipids and DTC risk using single-nucleotide polymorphisms (SNPs) from a genome-wide association (GWA) study containing a high-incidence Italian population of 690 cases samples with DTC and 497 controls. Results: Univariate and multivariate mendelian randomization analysis demonstrated that 'total cholesterol', 'HDL cholesterol', 'apolipoprotein B' and 'ratio of apolipoprotein B to apolipoprotein A1' were correlated with DTC. According to sensitivity analysis, our results were reliable. Furthermore, multivariate analysis revealed that there is no causative association between DTC and any of the many cause factors when they interact with one another, suggesting that there was a deep interaction between the four factors, which could affect each other. Finally, the mechanism of the related effects each other as well as the target genes with significant SNP regulatory effects in DTC was explored by conducting functional enrichment analysis and constructing the regulatory networks. Conclusions: We obtained four exposure factors (total cholesterol, HDL cholesterol, apolipoprotein B and ratio of apolipoprotein B to apolipoprotein A1) closely related to DTC, which laid a theoretical foundation for the treatment of DTC.

Adiponectin Stimulates Apolipoprotein A-1 Gene Expression in HepG2 Cells via AMPK, PPARα, and LXRs Signaling Mechanisms.

Adiponectin is an adipose tissue hormone, participating in energy metabolism and involved in atherogenesis. Previously, it was found that adiponectin increases expression of the APOA1 (apolipoprotein A-1) gene in hepatocytes, but the mechanisms of this effect remained unexplored. Our aim was to investigate the role of adiponectin receptors AdipoR1/R2, AMP-activated protein kinase (AMPK), nuclear peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptors (LXRs) in mediating the action of adiponectin on hepatic APOA1 expression in human hepatoma HepG2 cells. The level of APOA1 expression was determined by RT-qPCR and ELISA. We showed that the siRNA-mediated knockdown of genes coding for AdipoR1, AdipoR2, AMPK, PPARα, and LXRα and ß prevented adiponectin-induced APOA1 expression in HepG2 cells and demonstrated that interaction of PPARα and LXRs with the APOA1 gene hepatic enhancer is important for the adiponectin-dependent APOA1 transcription. The results of this study point out to the involvement of both types of adiponectin receptors, AMPK, PPARα, and LXRs in the adiponectin-dependent upregulation of the APOA1 expression.

Importance of Polymorphisms in the Gene of Paraoxonase-1 (SNP rs662) and Apolipoprotein A-I (SNP rs670 and rs5069) in Non-Smoking and Smoking Healthy Subjects and Patients with Acute Pancreatitis.

Oxidative stress has been implicated in the initiation of acute pancreatitis (AP). HDL is considered to be a preventing factor against cell membrane oxidation, thanks to the presence on its surface of apolipoprotein A-I (apoA-I) and paraoxonase-1 (PON1), which activity can be modified by genetic and environmental factors. The impact of SNP rs662 in the PON1 gene and SNP rs670 and rs5069 in the APOAI gene on PON1 activities and its concentration in the population of AP patients and healthy volunteers was investigated. In the group of patients with AP, a decreased HDL concentration and PON1 activities were observed. A decrease in the aryloesterase and lactonase activities of PON1 in AP patients with the TT genotype for SNP rs662 (especially in smokers) was found. In the group of patients with the AA genotype (rs670), the highest concentrations of HDL and apoA-I were observed, which were gradually decreasing in the course of AP. Changes in the concentration of apoA-I were associated with the changes in the concentration and activities of PON1 in the AP patients with the AA genotype for SNP rs670. A decreasing apoA-I concentration contributing to lowering PON1 concentration and its activities during the hospitalization of AP patients with the CC genotype for SNP rs5069 were shown. Therefore, more susceptibility of persons with the CC genotype for SNP rs5069 to pro/antioxidative imbalance was shown. In this process, an important role was played by the HDL level and its interaction with PON1 and apoA-I.

Leveraging knowledge of HDLs major protein ApoA1: Structure, function, mutations, and potential therapeutics.

Apolipoprotein A1 (ApoA1) is a member of the Apolipoprotein family of proteins. It's a vital protein that helps in the production of high-density lipoprotein (HDL) particles, which are crucial for reverse cholesterol transport (RCT). It also has anti-inflammatory, anti-atherogenic, anti-apoptotic, and anti-thrombotic properties. These functions interact to give HDL particles their cardioprotective characteristics. ApoA1 has recently been investigated for its potential role in atherosclerosis, diabetes, neurological diseases, cancer, and certain infectious diseases. Since ApoA1's discovery, numerous mutations have been reported that affect its structural integrity and alter its function. Hence these insights have led to the development of clinically relevant peptides and synthetic reconstituted HDL (rHDL) that mimics the function of ApoA1. As a result, this review has aimed to provide an organized explanation of our understanding of the ApoA1 protein structure and its role in various essential pathways. Furthermore, we have comprehensively reviewed the important ApoA1 mutations (24 mutations) that are reported to be involved in various diseases. Finally, we've focused on the therapeutic potentials of some of the beneficial mutations, small peptides, and synthetic rHDL that are currently being researched or developed, since these will aid in the development of novel therapeutics in the future.