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Advanced Science (Weinheim,... Jul 2022Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause...
Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG-VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte-specific deletion of MDM2 protects against high-fat high-cholesterol diet-induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG-VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein-protein interaction, which leads to reduced TG-VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2-ApoB interaction alleviates dietary-induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG-VLDL secretion. The effect of MDM2 on VLDL metabolism is p53-independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG-VLDL secretion in MAFLD. Inhibition of the MDM2-ApoB interaction may represent a potential therapeutic approach for MAFLD treatment.
Topics: Animals; Apolipoproteins B; Fatty Liver; Humans; Lipoproteins, VLDL; Liver; Mice; Obesity; Proteolysis; Proto-Oncogene Proteins c-mdm2; Triglycerides
PubMed: 35524581
DOI: 10.1002/advs.202200742 -
European Heart Journal Oct 2023The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to...
AIMS
The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved.
METHODS AND RESULTS
Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (apoB). Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 [95% confidence interval (CI): 1.99-3.36] and 1.37 [95% CI: 1.27-1.48], respectively. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster 2 contained SNPs in genes related to lipolysis that had a much greater effect on TRL/remnant-C. The CHD odds ratio per standard deviation (Sd) higher apoB for cluster 2 (with the higher TRL/remnant to LDL ratio) was 1.76 (95% CI: 1.58-1.96), which was significantly greater than the CHD odds ratio per Sd higher apoB in cluster 1 [1.33 (95% CI: 1.26-1.40)]. A concordant result was obtained by using polygenic scores for each cluster to relate apoB to CHD risk.
CONCLUSION
Distinct SNP clusters appear to impact differentially on remnant particles and LDL. Our findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL.
Topics: Humans; Cholesterol, LDL; Biological Specimen Banks; Triglycerides; Lipoproteins; Cholesterol; Apolipoproteins B; Coronary Disease; United Kingdom
PubMed: 37358553
DOI: 10.1093/eurheartj/ehad337 -
International Journal of Molecular... Apr 2019Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the...
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the disease progression is not clear, and there are no approved drugs to treat non-alcoholic steatohepatitis (NASH), the most advanced form of the disease. Thus, there is an urgent need for developing advanced in vitro human cellular systems to study disease mechanisms and drug responses. We attempted to create an organoid system genetically predisposed to NAFLD and to induce steatosis and fibrosis in it by adding free fatty acids. We used multilineage 3D spheroids composed by hepatocytes (HepG2) and hepatic stellate cells (LX-2) with a physiological ratio (24:1). HepG2 and LX-2 cells are homozygotes for the I148M sequence variant, the strongest genetic determinant of NAFLD. We demonstrate that hepatic stellate cells facilitate the compactness of 3D spheroids. Then, we show that the spheroids develop accumulations of fat and collagen upon exposure to free fatty acids. Finally, this accumulation was rescued by incubating spheroids with liraglutide or elafibranor, drugs that are in clinical trials for the treatment of NASH. In conclusion, we have established a simple, easy to handle, in vitro model of genetically induced NAFLD consisting of multilineage 3D spheroids. This tool may be used to understand molecular mechanisms involved in the early stages of fibrogenesis induced by lipid accumulation. Moreover, it may be used to identify new compounds to treat NASH using high-throughput drug screening.
Topics: Apolipoproteins B; Cell Lineage; Chalcones; Coculture Techniques; Collagen Type I; Fatty Acids; Hep G2 Cells; Humans; Liraglutide; Liver Cirrhosis; Models, Biological; Propionates; Spheroids, Cellular
PubMed: 30986904
DOI: 10.3390/ijms20071629 -
Journal of Atherosclerosis and... May 2022Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing...
AIM
Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan.
METHODS
Patients with LDL-C>190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative.
RESULTS
The mean age of the patients was 52.4±15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows: LDLR (n=395), APOB (n=58), PCSK9 (n=0), and ABCG5 (n=3). The most common mutations were APOB c.10579 C>T (p.R3527W) (12.6%), LDLR c.986 G>A (p.C329Y) (11.5%), and LDLR c.1747 C>T (p.H583Y) (10.8%). LDLR c.1187-10 G>A (IVS 8-10) and APOB c.10580 G>A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, including LDLR c.1060+2 T>C (IVS 7+2), LDLR c.1139 A>C (p.E380A), LDLR c.1322 T>C (p.A431T)+c.1867 A>G (p.I623V), and ABCG5 c.1337 G>A (p.R447Q).
CONCLUSION
LDLR and APOB, but not PCSK9, mutations were the major genetic causes of FH. Four novel mutations in LDLR or ABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.
Topics: Adult; Aged; Apolipoproteins B; DNA Mutational Analysis; Female; Genetic Testing; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Mutation; Phenotype; Proprotein Convertase 9; Receptors, LDL
PubMed: 33994402
DOI: 10.5551/jat.62773 -
The American Journal of Clinical... Jul 2019Dietary recommendations to limit red meat are based on observational studies linking intake to cardiovascular disease (CVD) risk together with the potential of its... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of red meat, white meat, and nonmeat protein sources on atherogenic lipoprotein measures in the context of low compared with high saturated fat intake: a randomized controlled trial.
BACKGROUND
Dietary recommendations to limit red meat are based on observational studies linking intake to cardiovascular disease (CVD) risk together with the potential of its saturated fatty acid (SFA) content to raise low-density lipoprotein (LDL) cholesterol. However, the relation of white meat to CVD risk, and the effects of dietary protein source on lipoprotein particle subfractions, have not been extensively evaluated.
OBJECTIVE
We tested whether levels of atherogenic lipids and lipoproteins differed significantly following consumption of diets with high red meat content compared with diets with similar amounts of protein derived from white meat or nonmeat sources, and whether these effects were modified by concomitant intake of high compared with low SFAs.
METHODS
Generally healthy men and women, 21-65 y, body mass index 20-35 kg/m2, were randomly assigned to 1 of 2 parallel arms (high or low SFA) and within each, allocated to red meat, white meat, and nonmeat protein diets consumed for 4 wk each in random order. The primary outcomes were LDL cholesterol, apolipoprotein B (apoB), small + medium LDL particles, and total/high-density lipoprotein cholesterol.
RESULTS
Analysis included participants who completed all 3 dietary protein assignments (61 for high SFA; 52 for low SFA). LDL cholesterol and apoB were higher with red and white meat than with nonmeat, independent of SFA content (P < 0.0001 for all, except apoB: red meat compared with nonmeat [P = 0.0004]). This was due primarily to increases in large LDL particles, whereas small + medium LDL and total/high-density lipoprotein cholesterol were unaffected by protein source (P = 0.10 and P = 0.51, respectively). Primary outcomes did not differ significantly between red and white meat. Independent of protein source, high compared with low SFA increased LDL cholesterol (P = 0.0003), apoB (P = 0.0002), and large LDL (P = 0.0002).
CONCLUSIONS
The findings are in keeping with recommendations promoting diets with a high proportion of plant-based food but, based on lipid and lipoprotein effects, do not provide evidence for choosing white over red meat for reducing CVD risk. This trial was registered at Clinicaltrials.gov as NCT01427855.
Topics: Adult; Apolipoproteins B; Atherosclerosis; Body Mass Index; Cholesterol, LDL; Cross-Over Studies; Dietary Fats; Dietary Proteins; Female; Humans; Lipoproteins; Male; Meat; Middle Aged; Particle Size; Red Meat
PubMed: 31161217
DOI: 10.1093/ajcn/nqz035 -
Current Opinion in Lipidology Dec 2019Determine if evidence supports interventions to prevent development of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) events and death. (Review)
Review
PURPOSE OF REVIEW
Determine if evidence supports interventions to prevent development of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) events and death.
RECENT FINDINGS
An extensive body of evidence supports the fundamental causal role of apolipoprotein B lipoproteins in the development of atherosclerosis. Recent epidemiologic studies have shown that LDL-cholesterol (LDL-C) and non-HDL-cholesterol levels in early adults are associated with accelerated subclinical atherosclerosis and an excess of atherosclerotic cardiovascular events later in life. Animal and human data have shown that intensive LDL-C lowering can regress earlier stages of atherosclerosis.
SUMMARY
The next research priority is evaluating the impact of lowering LDL-C earlier in life to regress early atherosclerosis, followed by trials to demonstrate this approach will eradicate later-life ASCVD events and death. This approach of curing atherosclerosis will likely be the most effective strategy for reducing the huge global burden of atherosclerosis.
Topics: Animals; Apolipoproteins B; Atherosclerosis; Cholesterol, LDL; Humans; Lipoproteins, HDL
PubMed: 31592794
DOI: 10.1097/MOL.0000000000000644 -
Lipids in Health and Disease Jul 2023Apolipoproteins and lipoprotein(a) are associated with various cardiometabolic diseases, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
Apolipoproteins and lipoprotein(a) are associated with various cardiometabolic diseases, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, among others. This systematic review and meta-analysis was conducted to evaluate the association of these markers with metabolic syndrome (MetS).
METHODS
We ran a systematic search through PubMed, Scopus, Embase, Ovid/Medline, and Web of Science on March 15, 2023. No language or date restrictions were applied. The only synthesised effect measure reported was the odds ratio (OR) with its corresponding 95% confidence interval (95% CI). We utilised the random-effects model for the quantitative synthesis.
RESULTS
We analysed 50 studies (n = 150 519) with different definitions for MetS. Increased ApoB values were associated with MetS (OR = 2.8; 95% CI: 2.44-3.22; p < 0.01, I = 99%). Decreased ApoA1 values were associated with MetS (OR = 0.42; 95% CI: 0.38-0.47; p < 0.01, I = 99%). Increased values of the ApoB/ApoA1 ratio were associated with MetS (OR = 4.97; 95% CI: 3.83-6.44; p < 0.01, I = 97%). Decreased values of Lp(a) were associated with MetS (OR = 0.89; 95% CI: 0.82-0.96; p < 0.01; I = 92%).
CONCLUSIONS
Increased values of ApoB and ApoB/ApoA1 ratio are associated with MetS, while decreased values of ApoA1 and Lp(a) are associated with MetS. These findings suggest that these lipid markers may serve as potential indicators for identifying subjects at risk of developing MetS. However, further research is required to elucidate the underlying mechanisms of these associations.
Topics: Humans; Metabolic Syndrome; Lipoprotein(a); Apolipoproteins; Apolipoproteins B; Insulin Resistance
PubMed: 37420190
DOI: 10.1186/s12944-023-01860-w -
BMC Musculoskeletal Disorders Nov 2023Lipids are critical in bone metabolism, and several studies have highlighted their importance. This study aimed to investigate the relationship between apolipoprotein B...
BACKGROUND
Lipids are critical in bone metabolism, and several studies have highlighted their importance. This study aimed to investigate the relationship between apolipoprotein B (apo B) and bone mineral density (BMD) at different skeletal sites (lumbar spine, femoral neck, and total femur) and to compare the influence of apo B with other traditional lipid markers.
METHODS
The study included participants from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2016 who had complete data for apo B and BMD at the three skeletal sites. We used weighted multivariate regression analysis, subgroup analysis, and interaction tests to examine associations. Restricted cubic spline (RCS) was used to examine the non-linear relationship.
RESULTS
A total of 4,258 adults were included in the study. Multivariate linear regression analysis showed that the relationship between apo B and BMD varied by skeletal site: a negative association was found with lumbar spine BMD [β = -0.054, 95%CI: (-0.073, -0.035)]. In contrast, a positive association was found with femoral neck BMD [β = 0.031, 95%CI: (0.011, 0.051)] and no significant association between apo B and total femur BMD.
CONCLUSIONS
Our findings suggest that apo B is associated with BMD in a site-specific manner.
Topics: Adult; Humans; Absorptiometry, Photon; Apolipoproteins B; Bone Density; Femur Neck; Lumbar Vertebrae; Nutrition Surveys
PubMed: 37919727
DOI: 10.1186/s12891-023-06990-x -
Journal of the American Heart... Aug 2023Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical... (Review)
Review
Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical care. This concern is misplaced. Our objective is to explain why and what the term "standardization" means. To produce clinically valid results, a test must accurately, precisely, and selectively measure the marker of interest. That is, it must be standardized. Accuracy refers to how closely the result obtained with 1 method corresponds to the result obtained with the standard method, precision to how reproducible the result is on repeated testing, and selectivity to how susceptible the method is to error by inclusion of other classes of lipoprotein particles. Multiple expert groups have determined that the measurement of apoB is adequately standardized for clinical care, and that apoB can be measured inexpensively, using widely available automated methods, more accurately, precisely, and selectively than low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. ApoB is a standard superior to low-density lipoprotein cholesterol and high-density lipoprotein cholesterol because it is a defined molecule, whereas the cholesterol markers are the mass of cholesterol within lipoprotein particles defined by their density, not by their molecular structure. Nevertheless, the standardization of apoB is being further improved by the application of mass spectrophotometric methods, whereas the limitations in the standardization and, therefore, the accurate, precise, and selective measurement of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are unlikely to be overcome. We submit that greater accuracy, precision, and selectivity in measurement is a decisive advantage for apoB in the modern era of intensive lipid-lowering therapies.
Topics: Cholesterol, LDL; Cholesterol; Apolipoproteins B; Apolipoprotein B-100; Cholesterol, HDL; Lipoproteins; Apolipoprotein A-I
PubMed: 37489721
DOI: 10.1161/JAHA.123.030405 -
BMC Medicine Jul 2023Asialoglycoprotein receptor 1 (ASGR1) is emerging as a potential drug target to reduce low-density lipoprotein (LDL)-cholesterol and coronary artery disease (CAD) risk....
Genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and health outcomes: a drug-target Mendelian randomization study and a phenome-wide association study.
BACKGROUND
Asialoglycoprotein receptor 1 (ASGR1) is emerging as a potential drug target to reduce low-density lipoprotein (LDL)-cholesterol and coronary artery disease (CAD) risk. Here, we investigated genetically mimicked ASGR1 inhibitors on all-cause mortality and any possible adverse effects.
METHODS
We conducted a drug-target Mendelian randomization study to assess genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and 25 a priori outcomes relevant to lipid traits, CAD, and possible adverse effects, i.e. liver function, cholelithiasis, adiposity and type 2 diabetes. We also performed a phenome-wide association study of 1951 health-related phenotypes to identify any novel effects. Associations found were compared with those for currently used lipid modifiers, assessed using colocalization, and replicated where possible.
RESULTS
Genetically mimicked ASGR1 inhibitors were associated with a longer lifespan (3.31 years per standard deviation reduction in LDL-cholesterol, 95% confidence interval 1.01 to 5.62). Genetically mimicked ASGR1 inhibitors were inversely associated with apolipoprotein B (apoB), triglycerides (TG) and CAD risk. Genetically mimicked ASGR1 inhibitors were positively associated with alkaline phosphatase, gamma glutamyltransferase, erythrocyte traits, insulin-like growth factor 1 (IGF-1) and C-reactive protein (CRP), but were inversely associated with albumin and calcium. Genetically mimicked ASGR1 inhibitors were not associated with cholelithiasis, adiposity or type 2 diabetes. Associations with apoB and TG were stronger for ASGR1 inhibitors compared with currently used lipid modifiers, and most non-lipid effects were specific to ASGR1 inhibitors. The probabilities for colocalization were > 0.80 for most of these associations, but were 0.42 for lifespan and 0.30 for CAD. These associations were replicated using alternative genetic instruments and other publicly available genetic summary statistics.
CONCLUSIONS
Genetically mimicked ASGR1 inhibitors reduced all-cause mortality. Beyond lipid-lowering, genetically mimicked ASGR1 inhibitors increased liver enzymes, erythrocyte traits, IGF-1 and CRP, but decreased albumin and calcium.
Topics: Humans; Apolipoproteins B; Asialoglycoprotein Receptor; Calcium; Cholelithiasis; Coronary Artery Disease; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Insulin-Like Growth Factor I; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Factors; Triglycerides
PubMed: 37400795
DOI: 10.1186/s12916-023-02903-w