👤 Joan Khoo

Apolipoprotein B [apoB] and lipoprotein(a) [Lp(a)] concentrations are the two prime lipoprotein indices recommended by some expert consensus to assess and manage cardiovascular risk. However, their distributions, associations, inter-relationships, and clinical relevance remain un-investigated in the majority of Asian populations, particularly among healthcare workers. The distributions and relationships of serum Lp(a), apoB, and other lipid biomarker concentrations in 1,927 Asian consenting healthcare workers across ethnicities, sexes, and body mass index (BMI) were analysed. The percentage of apoB content of Lp(a) relative to apoB particle concentrations (Lp(a)-to-apoB proportion) was calculated. Participants’ mean age was 39.4 years, mostly females (79.7%). Ethnicities were Chinese (57.2%), Malay (16.9%), Indian (9.2%), Filipino (12.8%) and others (3.8%). Distribution of Lp(a) was positively skewed to the right for all ethnicities. The median Lp(a) was 16.4 nmol/L (IQR 7.9, 41.8) and ranged between < 7 to 470 nmol/L. The proportion of participants with Lp(a) ≥ 75 nmol/L was 13.9%, and with Lp(a) ≥ 125 nmol/L was 7.8%. Multivariable linear regression analysis showed that being female, older age, and Indian ethnicity were associated with higher Lp(a) levels, whereas being male, older age, Indian ethnicity, and higher BMI were associated with higher mean apoB levels. In this cohort, 11.4% of individuals had Lp(a)-to-apoB proportion > 5%, whilst 3.3% had Lp(a)-to-apoB proportion of > 10%. Among individuals with Lp(a) ≥ 250 nmol/L, the median Lp(a)-to-apoB proportion was 14.9% (IQR 12.6,19.7). Across Lp(a) deciles, the Lp(a)-to-apoB proportions were inversely correlated with LDL-C, non-HDL-C, remnant cholesterol, and triglyceride concentrations. Abnormal Lp(a) (≥ 75 nmol/L) was found in 13.9% of a predominantly female Asian healthcare cohort. In individuals with Lp(a) ≥ 250 nmol/L, Lp(a) particles contributed to the circulating apoB levels by a median of 15%. These findings support the notion that Lp(a) should be integrated into routine lipid assessment in Asian populations, including healthcare workers. clinicaltrial.gov NCT06304415. The online version contains supplementary material available at 10.1186/s12944-026-02912-7. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that apolipoprotein E (APOE) polymorphism and dysregulated ceramide metabolism are critical links among these pathogenic processes. Ceramide accumulation in the brain contributes to Aβ generation, tau phosphorylation, and neuronal apoptosis. Elevated ceramide levels have been observed in plasma, cerebrospinal fluid, and peripheral organs such as the liver, reflecting systemic lipid dysregulation. Lipoproteins-particularly low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)-transport ceramide across the blood-brain barrier, while apoE4 isoforms exacerbate this process by disrupting vascular integrity and lipid homeostasis. In addition, hepatic and gut-derived ceramides may influence neurodegeneration through the liver-gut-brain axis. Therapeutic interventions targeting ceramide synthesis (serine palmitoyltransferase inhibitors), production (neutral sphingomyelinase inhibitors), and the ceramide/sphingosine-1-phosphate (S1P) balance show potential in preclinical models for reducing Aβ pathology, tau aggregation, and neuroinflammation. These findings position ceramide metabolism as a critical mediator of AD pathogenesis and a promising target for diagnosis and treatment. Modulating ceramide and S1P signaling could complement current amyloid- and tau-directed therapies, offering new opportunities for disease modification and early intervention. Show less

Adherence to antiretroviral therapy is essential for achieving viral suppression. Plasma separation cards (HemaSep; HS-DBS) provide advantages for pharmacokinetic (PK) analysis and adherence monitoring, including simplified sample collection. This study compared the PK of dolutegravir (DTG), nucleoside reverse transcriptase inhibitors (NRTIs), and their intracellular metabolites in the dried plasma and cellular fractions of HS-DBS against the appropriate gold-standard matrices: liquid plasma for parent drugs and Whatman DBS (WM-DBS) for NRTI metabolites. The APT-POCT-01 clinical trial (NCT04302896) is an open-label study assessing drug concentrations following cessation in healthy volunteers. Participants were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Paired liquid plasma (L-pL), HS-DBS, and WM-DBS samples were collected on Day 15 and following treatment cessation (0-336 hours post-final dose). 29 individuals were included in the PK analysis (15-TDF/14-TAF). Tenofovir diphosphate (TFV-DP) was quantifiable up to 14 days post-cessation in HS-DBS (TAF/TDF) and WM-DBS (TDF) (HS-DBS t½ > 17 days, WM-DBS t½ = 15 days). 3TC-TP and FTC-TP were eliminated more rapidly. Nucleoside di/triphosphate concentrations were 3-7-fold higher, with prolonged half-lives (TFV-DP, FTC-TP), compared with WM-DBS. TFV-DP levels were ~12-fold higher with TDF compared to TAF. For NRTI and DTG, HS-plasma resulted in 1.8-fold higher exposures compared to L-pL. Measurable HS-DBS concentrations were correlated with L-pL and WM-DBS, with Bland-Altman analysis indicating agreement between methods. This study provides important insights into the elimination kinetics of NRTI, their intracellular metabolites and DTG. Plasma separation cards are a promising alternative for adherence monitoring, enabling simultaneous quantification of parent and intracellular moieties from a single sample. Differences in TFV-DP levels between TDF and TAF regimens, and DBS sampling method, underscore the need for matrix and regimen-specific interpretation to validate adherence benchmarks. Show less

Introduction: Pathogenic heterozygous melanocortin-4 receptor (MC4R) variants are the most common cause of monogenic obesity, affecting central satiety and appetite regulatory areas of the brain. Case Presentations: We report a pedigree with a pathogenic MC4R variant (c.380C>T, p.Ser127Leu). In the proband with obesity (BMI 35 kg/m2) and severe insulin resistance, use of combination of semaglutide and naltrexone-bupropion was successful in reducing insulin requirements and weight. His adult monozygotic twin daughters both had childhood-onset obesity; however, weight trajectories differed. Twin 1 had a peak BMI of 29.1 kg/m2, which decreased to 19.7 kg/m2 with intensive exercise and diet control without weight-lowering medication. Twin 2 had a sedentary lifestyle and epilepsy and had a peak BMI of 30.1 kg/m2; she responded well to naltrexone-bupropion and BMI decreased to 26 kg/m2. Conclusion: The manifestation of obesity, even in cases of monogenic obesity, can vary significantly due to the influence of environmental and lifestyle factors.

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Humans spend much of the day in the postprandial state. However, most research and clinical guidelines on plasma lipids pertain to blood drawn after a 12-hour fast. We aimed to study the metabolic differences of apoB lipoproteins between the fasting and postprandial states. We investigated plasma apoB metabolism using stable isotope tracers in 12 adult volunteers under fasting and continuous postprandial conditions in a randomized crossover study. We determined the metabolism of apoB in multiple lipoprotein subfractions, including light and dense VLDLs (very-low-density lipoproteins), IDLs (intermediate-density lipoproteins), and light and dense LDLs (low-density lipoproteins) that do or do not contain apoE or apoC3. A major feature of the postprandial state is 50% lower secretion rate of triglyceride-rich lipoproteins and concurrent slowdown of their catabolism in circulation, as shown by 34% to 55% lower rate constants for the metabolic pathways of conversion by lipolysis from larger to smaller lipoproteins and direct clearance of lipoproteins from the circulation. In addition, the secretion pattern of apoB lipoprotein phenotypes was shifted from particles containing apoE and apoC3 in the fasting state to those without either protein in the postprandial state. Overall, during the fasting state, hepatic apoB lipoprotein metabolism is activated, characterized by increased production, transport, and clearance. After food intake, endogenous apoB lipoprotein metabolism is globally reduced as appropriate to balance dietary input to maintain the supply of energy to peripheral tissues. Show less

In mammals, HP1-mediated heterochromatin forms positionally and mechanically stable genomic domains even though the component HP1 paralogs, HP1α, HP1β, and HP1γ, display rapid on-off dynamics. Here, we investigate whether phase-separation by HP1 proteins can explain these biological observations. Using bulk and single-molecule methods, we show that, within phase-separated HP1α-DNA condensates, HP1α acts as a dynamic liquid, while compacted DNA molecules are constrained in local territories. These condensates are resistant to large forces yet can be readily dissolved by HP1β. Finally, we find that differences in each HP1 paralog's DNA compaction and phase-separation properties arise from their respective disordered regions. Our findings suggest a generalizable model for genome organization in which a pool of weakly bound proteins collectively capitalize on the polymer properties of DNA to produce self-organizing domains that are simultaneously resistant to large forces at the mesoscale and susceptible to competition at the molecular scale. Show less