Lipophagy is a form of selective autophagy that targets the lipid droplets for lysosomal decay and has been implicated in the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Factors that augment lipophagy have been identified as targets for MASLD therapeutic development. TMEM55B is a key regulator of lysosomal positioning, which is critical for lysosome fusion with the autophagosome, but is less well studied. Here, we demonstrate that the absence of TMEM55B in murine models accelerates MASLD onset and progression to metabolic dysfunction-associated steatohepatitis (MASH). In cellular models, TMEM55B deficiency enhances incomplete lipophagy, whereby lysosome-lipid droplet interactions are increased, but lysosomal cargo is not fully degraded and/or released, leading to the development of lipid-filled lysosomes (lipolysosomes). Loss of TMEM55B also impairs mitophagy, causing an accumulation of dysfunctional mitochondria. This imbalance leads to increased lipid accumulation and oxidative stress, worsening MASLD. These findings underscore the importance of lysosomal positioning in lipid metabolism and suggest that targeting lipophagy for MASLD therapeutic development should be carefully considered to ensure promotion of the entire lipophagic flux pathway and whether it occurs in the context of mitochondrial dysfunction.

Statins are a commonly prescribed cholesterol lowering drug class that can increase the risk of new-onset diabetes (NOD). To investigate the molecular mechanisms underlying this effect, we generated human induced pluripotent stem cells (iPSCs) from individuals identified from electronic health records of Kaiser Permanente of Northern California who were susceptible to developing NOD after statin initiation or controls who maintained stable fasting glucose on statin treatment. RNA-seq analysis of iPSCs incubated with atorvastatin, simvastatin or mock buffer for 24 hours identified the long non-coding RNA MIR194-2HG as a top candidate gene. Statin-induced increases in its expression were observed in NOD resistant controls, while statin-induced reductions occurred in NOD susceptible cases. MIR194-2HG encompasses two microRNA genes: MIR192 and MIR194-2 . The mature microRNA miR-192-5p, derived from the 5' arm of MIR192 , was predicted to bind the 3'UTR of the glucagon like peptide 1 (GLP-1) receptor ( GLP1R ) transcript. Transfection of a rat insulinoma cell line INS-1 with a miR-192-5p mimic increased Glp1r transcript (1.41-fold) and protein (1.51-fold) levels compared to a scrambled control. Using a luciferase reporter containing the human GLP1R 3'UTR, miR-192-5p overexpression similarly increased luciferase signal (1.44-fold). The miR-192-5p mimic enhanced glucose stimulated insulin secretion (GSIS) in response to GLP1R agonists (1.64-1.81-fold) and rescued simvastatin-induced GSIS impairment in INS-1 cells. Wild-type mice treated with miR-192 AAV8 had improved glucose sensitivity. Islets isolated from these mice exhibited enhanced GLP-1 potentiated GSIS during perifusion ex vivo . These effects were absent in the DIRKO ( Glp1r/Gipr double knockout) mouse islets, consistent with the idea that miR-192 promotes GLP-1 mediated GSIS through GLP1R. These findings implicate MIR192 in statin-induced impairment of GSIS by modulating GLP1R, potentially contributing to the susceptibility to NOD in statin users.

Context The Early vs Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced atherosclerosis progression among early but not late postmenopausal women (PMW).Objective Determined by time-since-menopause (1) HT effects on lipids and lipoprotein particle subfractions (LPs), (2) associations of estradiol (E2) level with lipids and LPs, (3) associations of lipids and LPs with atherosclerosis progression.Design Randomized controlled trial stratified by time-since-menopause.Setting Academic institution.Participants Healthy postmenopausal women.Intervention Oral E2 with/without sequential vaginal progesterone.Main Outcome Measures Standard lipids and 21 LPs quantitated by ion mobility every 6 months.Results Among 562 PMW (240 early, 322 late), HT significantly increased total triglycerides (TG), high-density lipoprotein (HDL) cholesterol, small low-density lipoproteins (LDL), large HDL, and TG/C ratio in LDL and HDL and decreased LDL-cholesterol, total very low density lipoproteins (VLDL), small VLDL, intermediate-density lipoproteins, large LDL, and LDL peak diameter. HT showed no lipid or LP differences between time-since-menopause. Associations of E2 level with lipids and LPs explained the HT effects. Despite the nonsignificant P interaction by time-since-menopause, we observed that very small LDL and total HDL LPs were associated with atherosclerosis progression in late PMW.Conclusion HT effects on standard lipids and LPs are consistent with the literature. HT has similar effect on lipids and LPs in early and late PMW. Novel findings include discordant effects of HT on TG and VLDL particles, which can be explained by increased catabolism of atherogenic remnants of TG-rich lipoproteins. Our findings extend the well-known HT effects on standard lipids and LPs that may contribute to the beneficial effects on atherosclerosis progression in PMW.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

BACKGROUND AND OBJECTIVES:Previous research of associations between statins and Alzheimer disease and Alzheimer disease-related dementias (AD/ADRDs) has been limited by short follow-up, small samples, and confounding. We aimed to estimate the association between the 1st statin prescription and incident AD/ADRD among members of a large population-based cohort of older adults. METHODS:We used a cohort study design emulating a target trial using data from Kaiser Permanente Northern California (KPNC), an integrated health care delivery system. Participants were born before 1951 and KPNC members for 4+ years during 1997-2010. Embedded subsamples included sociodemographic and genetic data. Statin initiators were matched at first prescription ("baseline") with up to 5 "noninitiators" based on age and low-density lipoprotein cholesterol (LDL-C). Participants with extreme propensity scores were excluded. The outcome was time to incident AD/ADRD diagnosis, censoring, or the administrative end of study (December 31, 2020). Cox proportional hazard models were used to estimate hazard ratios for statin initiation on AD/ADRD incidence. Follow-up time was divided at the first year of follow-up to account for increased AD/ADRD detection in the first year due to increased interaction with the health care system after a statin prescription. RESULTS:Among eligible participants (n = 705,061), 264,294 individuals (37.5% of eligible participants) initiated any statin during 2001-2010 ("initiators"), of whom 249,613 (94.4%) were matched with 255,937 unique noninitiators to create the analytic sample (322,358 unique participants; mean age at baseline = 67.4 years; 55.1% female). The average follow-up was 11.8 years. In the first year after initiating statins, AD/ADRD diagnoses were elevated by 46% (hazard ratio [HR] = 1.46, 95% CI 1.42-1.53) compared with noninitiators. After 1 year, statin initiators experienced no difference in AD/ADRD incidence (full sample: HR = 1.00, 95% CI 0.99-1.01; subsample with survey covariates: HR = 1.01, 95% CI 0.98-1.06; subsample with survey and genetic covariates: HR = 0.97, 95% CI 0.91-1.07). Adjustment for sociodemographic covariates and apolipoprotein E e4 allele count did not materially change the findings. DISCUSSION:In this large emulated target trial, statin initiation was inconsistent with more than a 3% increase or decrease in the hazard of AD/ADRD after the first year of follow-up. This intent-to-treat analysis does not directly quantify effects of long-term exposure to statins. Associations in the first year likely reflect increased medical observation immediately after statin initiation. CLASSIFICATION OF EVIDENCE:This emulated trial provides Class II evidence that statin initiation is not associated with AD/ADRD or AD incidence after the first year of follow-up.

Most current dietary guidelines for the prevention of cardiovascular diseases (CVD) recommend the consumption of low-fat dairy in place of regular-fat dairy foods, one of the main sources of dietary saturated fatty acids (SFAs). Here, we summarize the data presented and discussions held-relating to the validity of such recommendations-between a panel of international nutrition research experts at a high-level closed workshop on "Saturated Fat in Dairy and Cardiovascular Diseases," which took place in Amsterdam on 15-16 April, 2024. The most recent evidence indicates that overall, consumption of milk, yogurt and cheese, irrespective of fat content, is neutrally associated with CVD risk. There is also no evidence yet from randomized controlled trials that consumption of regular-fat milk, yogurt, and cheese has different effects on a broad array of cardiometabolic risk factors when compared with consumption of low-fat milk, yogurt, and cheese. Thus, the body of evidence does not support differentiation between regular-fat and low-fat dairy foods in dietary guidelines for both adults and children. Strategies focusing primarily on reduction of energy-dense, nutrient-poor foods, the main source of SFAs in Western diets, rather than on the fat content of dairy foods, are more likely to benefit the population's cardiovascular health. Future research is needed to understand better the place of regular-fat and low-fat dairy foods within healthy eating patterns.

INTRODUCTION:We evaluated the independent associations between high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels with Alzheimer's disease and related dementias (ADRD). METHODS:Among 177,680 members of Kaiser Permanente Northern California who completed a survey on health risks, we residualized TGs and HDL-C conditional on age, sex, and body mass index. We included these residuals individually and concurrently in Cox models predicting ADRD incidence. RESULTS:Low (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02-1.10) and high quintiles (HR 1.07, 95% CI 1.03-1.12) of HDL-C residuals were associated with an increased risk of ADRD compared to the middle quintile. Additional adjustment for TGs attenuated the association with high HDL-C (HR 1.03, 95% CI 0.99-1.08). Low TG residuals were associated with an increased ADRD risk (HR 1.10, 95% CI 1.06-1.15); high TG residuals were protective (HR 0.92, 95% CI 0.88-0.96). These estimates were unaffected by HDL-C adjustment. DISCUSSION:Low HDL-C and TG levels are independently associated with increased ADRD risk. The correlation with low TG level explains the association of high HDL-C with ADRD. HIGHLIGHTS:Strong correlations between lipid levels are important considerations when investigating lipids as late-life risk factors for Alzheimer's disease and related dementias (ADRD). Low levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) were independently associated with an increased risk of ADRD. We found no evidence for an association between high HDL-C and increased ADRD risk after adjustment for TGs. High levels of TGs were consistently associated with a decreased risk of ADRD. There may be interaction between TG and HDL-C levels, where both low HDL-C and TG levels increase the risk of ADRD compared to average levels of both.

Atherogenesis has been shown in mice to be dependent on activation of the NLRP3 inflammasome, a cytosolic innate immune sensor activated by a broad range of pathogen and damage associated molecular patterns, including oxidized LDL (oxLDL) in atherosclerosis. Previous work from our group has shown that knockdown of Translocase of Outer Mitochondrial Membrane 40 ( TOMM40), which encodes a component of the mitochondrial importer TOM complex, increases expression and activity of the nuclear receptor-family transcription factor, liver X receptor (LXR) in hepatocytes. As LXR agonists have been shown to inhibit NLRP3 activation, we confirmed the prediction that TOMM40 knockdown has this effect in THP-1 monocyte-derived macrophages. Further, we demonstrated that TOMM40 KD upregulates LXR-mediated macrophage expression of the ABCA1 and ABCG1 genes which encode transporters that promote cellular cholesterol efflux, the first step in reverse cholesterol transport to the liver. Taken together, these findings identify a novel mechanism whereby increased LXR activity induced by suppression of TOMM40 expression in macrophages may retard atherogenesis both by inhibiting inflammation and promoting reverse cholesterol transport. ### Competing Interest Statement The authors have declared no competing interest.

INTRODUCTION:Mixed evidence on how statin use affects risk of Alzheimer's disease and related dementias (ADRD) may reflect heterogeneity across sociodemographic factors. Few studies have sufficient power to evaluate effect modifiers. METHODS:Kaiser Permanente Northern California (KPNC) members (n = 705,061; n = 202,937 with sociodemographic surveys) who initiated statins from 2001 to 2010 were matched on age and low-density lipoprotein cholesterol (LDL-C) with non-initiators and followed through 2020 for incident ADRD. Inverse probability-weighted Cox proportional hazards models were used to evaluate effect modification by age, gender, race/ethnicity, education, marital status, income, and immigrant generation. RESULTS:Statin initiation (vs non-initiation) was not associated with ADRD incidence in any of the 32 subgroups (p > .05). Hazard ratios ranged from 0.964 (95% CI: 0.923 to 1.006) among Asian-identified participants to 1.122 (95% CI: 0.995 to 1.265) in the highest income category. DISCUSSION:Sociodemographic heterogeneity appears to have little to no influence on the relationship between statin initiation and dementia. HIGHLIGHTS:The study includes a large and diverse cohort from Kaiser Permanente (N = 705,061). An emulated trial design of statin initiation on dementia incidence was used. Effect modification by sociodemographic factors was assessed. There were no significant Alzheimer's disease and related dementias (ADRD) risk differences in 32 sociodemographic subgroups (p > 0.05).

Mixed evidence on how statins affect dementia risk may reflect variability in model specifications. Alternate specifications are rarely systematically compared. Using an emulated trial design framework, we investigated variation in the estimated effect of statin initiation on dementia across alternative (1) eligibility criteria, (2) confounding variable sets, and (3) outcome definitions. Kaiser Permanente Northern California members’ linked electronic health records from 1996 to 2020 were used to identify statin initiation and dementia diagnoses. Statin initiators were matched on age and low-density lipoprotein cholesterol with up to 5 non-initiators. Possible covariates included clinical (n = 1.4 million); socioeconomic and behavioral (n = 265,224); and genetic (n = 69,573) variables. Using Cox proportional-hazards models, we estimated variation across 1.27 million intent-to-treat estimates for statin initiation varying specification of eligibility, outcome definition, and covariates. Estimated hazard ratios (HRs) for statin initiation on dementia across all specifications ranged from 0.93 to 1.47. The variance of estimates due to model specification differences was 7.6 times larger than the average variance of specific estimates due to finite sample size. Three modeling decisions notably attenuated coefficients [ln(HR)]: requiring a run-in period prior to the emulated trial start date (0.034); adjustment for diabetes (0.030) and cardiovascular disease (0.039); and excluding the first year of follow-up (0.041). HRs from models with all three specifications ranged from 0.99 to 1.15. No specification we evaluated consistently generated protective effects. Estimates of the association between statin initiation and dementia leveraging real world data are sensitive to model specification, especially decisions related to clinical covariates and time-at-risk.

Statin pharmacogenetic implementation guidelines are derived from evidence of primarily Eurocentrically biased study populations. Functional SLCO1B1 variants that are rare in these study populations have not been equitably investigated and are thus missing from guidelines. The objective of this precision medicine health equity study was to determine the clinical validity of understudied candidate functional SLCO1B1 variants common in people with 1,000 Genomes sub-Saharan African superpopulation (1KG-AFR-like) genetic similarity. We conducted our analyses using the real-world evidence of participants from three large, electronic health record-linked biobanks. We used bilirubin levels (as an endogenous substrate of organic anion transporting polypeptide [OATP1B1] function) and severe statin-induced myotoxicity phenotypes. Loss-of-function splice variant rs77271279 (P = 1.1 × 10-17) had the strongest association with elevated total bilirubin levels in Black participants (mean 84% AFR-like genetic similarity) followed by missense variant rs59502379 (P = 7.4 × 10-12) then missense variant rs4149056 (P = 6.0 × 10-5). In an exploratory subset of the Black study population who used statins (n = 77 severe statin-induced myotoxicity cases), rs59502379 (odds ratio [OR] = 2.85, 95% confidence interval [CI] 1.08-7.52), but not rs77271279 (OR = 1.75, 95% CI 0.62-4.73) was associated with myotoxicity. Sensitivity analyses in participants with >5% AFR-like genetic similarity corroborated these findings. For white participants, rs77271279 and rs59502379 were rare precluding subsequent analyses. Our findings highlight the clinical relevance for understudied SLCO1B1 variants on pharmacogenetic testing panels with a potential immediate impact on reducing the risk of severe statin-induced myotoxicity primarily in Black patients, a group historically excluded from genomic research. Future studies require larger statin user study populations with less heterogeneity by statin type.

Background and ObjectivesPrevious research of associations between statins and Alzheimer disease and Alzheimer disease-related dementias (AD/ADRDs) has been limited by short follow-up, small samples, and confounding. We aimed to estimate the association between the 1st statin prescription and incident AD/ADRD among members of a large population-based cohort of older adults.MethodsWe used a cohort study design emulating a target trial using data from Kaiser Permanente Northern California (KPNC), an integrated health care delivery system. Participants were born before 1951 and KPNC members for 4+ years during 1997-2010. Embedded subsamples included sociodemographic and genetic data. Statin initiators were matched at first prescription ("baseline") with up to 5 "noninitiators" based on age and low-density lipoprotein cholesterol (LDL-C). Participants with extreme propensity scores were excluded. The outcome was time to incident AD/ADRD diagnosis, censoring, or the administrative end of study (December 31, 2020). Cox proportional hazard models were used to estimate hazard ratios for statin initiation on AD/ADRD incidence. Follow-up time was divided at the first year of follow-up to account for increased AD/ADRD detection in the first year due to increased interaction with the health care system after a statin prescription.ResultsAmong eligible participants (n = 705,061), 264,294 individuals (37.5% of eligible participants) initiated any statin during 2001-2010 ("initiators"), of whom 249,613 (94.4%) were matched with 255,937 unique noninitiators to create the analytic sample (322,358 unique participants; mean age at baseline = 67.4 years; 55.1% female). The average follow-up was 11.8 years. In the first year after initiating statins, AD/ADRD diagnoses were elevated by 46% (hazard ratio [HR] = 1.46, 95% CI 1.42-1.53) compared with noninitiators. After 1 year, statin initiators experienced no difference in AD/ADRD incidence (full sample: HR = 1.00, 95% CI 0.99-1.01; subsample with survey covariates: HR = 1.01, 95% CI 0.98-1.06; subsample with survey and genetic covariates: HR = 0.97, 95% CI 0.91-1.07). Adjustment for sociodemographic covariates and apolipoprotein E e4 allele count did not materially change the findings.DiscussionIn this large emulated target trial, statin initiation was inconsistent with more than a 3% increase or decrease in the hazard of AD/ADRD after the first year of follow-up. This intent-to-treat analysis does not directly quantify effects of long-term exposure to statins. Associations in the first year likely reflect increased medical observation immediately after statin initiation.Classification of EvidenceThis emulated trial provides Class II evidence that statin initiation is not associated with AD/ADRD or AD incidence after the first year of follow-up.

Objective:Considering the non-specific nature of muscle symptoms, studies of statin-induced myopathy (SIM) in electronic health records require accurate algortihms that can reliably identify true statin-related cases. However, prior algorithms have been constructed in study populations that preclude broad applicability. Here we developed and validated an algorithm that accurately defines SIM from electronic health records using structured data elements and conducted a study of determinants of SIM after applying the algorithm. Materials and Methods:We used electronic records from an integrated health care delivery system (including comprehensive pharmacy dispensing records) and defined SIM as elevated creatine kinase (CK) ≥4 x upper limit of normal. A diverse cohort of participants receiving a variety of statin regimens met the criteria for study inclusion. Results:We identified multiple conditions strongly associated with elevated CK independent of statin use. A 2-step algorithm was developed using these all-cause conditions as secondary causes (step 1) along with evidence of a statin regimen change (step 2). We identified 1,262 algorithm-derived statin-induced elevated CK cases. Gold standard SIM cases determined from manual chart reviews on a random subset of the all-cause elevated CK cases were used to validate the algorithm, which had a 76% sensitivity and 77% specificity for detecting the most certain cases. Pravastatin use was associated with a 2.18 odds (95% confidence interval 1.39-3.40, P=0.0007) for statin-induced CK elevation compared to lovastatin use after adjusting for dose and other factors. Conclusions:We have produced an efficient, easy-to-apply methodological tool that can improve the quality of future research on statin-induced myopathy.

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes and muscle weakness. Here the authors show that statin-treated female mice show reduced levels of docosahexaenoic acid (DHA) and that the adverse effects are prevented by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene.

Objective The gene encoding TOMM40 (Transporter of Outer Mitochondrial Membrane 40) is adjacent to that encoding APOE, which has a central role in lipid and lipoprotein metabolism. While human genetic variants near APOE and TOMM40 have been shown to be strongly associated with plasma lipid levels, a specific role for TOMM40 in lipid metabolism has not been established, and the present study was aimed at assessing this possibility. Methods TOMM40 was knocked down by siRNA in human hepatoma HepG2 cells, and effects on mitochondrial function, lipid phenotypes, and crosstalk between mitochondria, ER, and lipid droplets were examined. Additionally, hepatic and plasma lipid levels were measured in mice following shRNA-induced knockdown of Tomm40 shRNA. Results In HepG2 cells, TOMM40 knockdown upregulated expression of APOE and LDLR in part via activation of LXRB (NR1H2) by oxysterols, with consequent increased uptake of VLDL and LDL. This is in part due to disruption of mitochondria-endoplasmic reticulum contact sites, with resulting accrual of reactive oxygen species and non-enzymatically derived oxysterols. With TOMM40 knockdown, cellular triglyceride and lipid droplet content were increased, effects attributable in part to receptor-mediated VLDL uptake, since lipid staining was significantly reduced by concomitant suppression of either LDLR or APOE. In contrast, cellular cholesterol content was reduced due to LXRB-mediated upregulation of the ABCA1 transporter as well as increased production and secretion of oxysterol-derived cholic acid. Consistent with the findings in hepatoma cells, in vivo knockdown of TOMM40 in mice resulted in significant reductions of plasma triglyceride and cholesterol concentrations, reduced hepatic cholesterol and increased triglyceride content, and accumulation of lipid droplets leading to development of steatosis. Conclusions These findings demonstrate a role for TOMM40 in regulating hepatic lipid and plasma lipoprotein levels and identify mechanisms linking mitochondrial function with lipid metabolism.

B cell malignancies, comprising over 80 heterogeneous blood cancers, pose significant prognostic challenges due to intricate oncogenic signaling. Emerging evidence emphasizes the pivotal role of disrupted lipid metabolism in the development of these malignancies. Variations in lipid species, such as phospholipids, cholesterol, sphingolipids, and fatty acids, are widespread across B cell malignancies, contributing to uncontrolled cell proliferation and survival.Phospholipids play a crucial role in initial signaling cascades leading to B cell activation and malignant transformation through constitutive B cell receptor (BCR) signaling. Dysregulated cholesterol and sphingolipid homeostasis support lipid raft integrity, crucial for propagating oncogenic signals. Sphingolipids impact malignant B cell stemness, proliferation, and survival, while glycosphingolipids in lipid rafts modulate BCR activation. Additionally, cancer cells enhance fatty acid-related processes to meet heightened metabolic demands. In obese individuals, the obesity-derived lipids and adipokines surrounding adipocytes rewire lipid metabolism in malignant B cells, evading cytotoxic therapies. Genetic drivers such as MYC translocations also intrinsically alter lipid metabolism in malignant B cells.In summary, intrinsic and extrinsic factors converge to reprogram lipid metabolism, fostering aggressive phenotypes in B cell malignancies. Therefore, targeting altered lipid metabolism has translational potential for improving risk stratification and clinical management of diverse B cell malignancy subtypes.

The ketogenic diet (KD, also known as metabolic therapy) has been successful in the treatment of obesity, type 2 diabetes, and epilepsy. More recently, this treatment has shown promise in the treatment of psychiatric illness. We conducted a 4-month pilot study to investigate the effects of a KD on individuals with schizophrenia or bipolar disorder with existing metabolic abnormalities. Twenty-three participants were enrolled in a single-arm trial. Results showcased improvements in metabolic health, with no participants meeting metabolic syndrome criteria by study conclusion. Adherent individuals experienced significant reduction in weight (12 %), BMI (12 %), waist circumference (13 %), and visceral adipose tissue (36 %). Observed biomarker enhancements in this population include a 27 % decrease in HOMA-IR, and a 25 % drop in triglyceride levels. In psychiatric measurements, participants with schizophrenia showed a 32 % reduction in Brief Psychiatric Rating Scale scores. Overall Clinical Global Impression (CGI) severity improved by an average of 31 %, and the proportion of participants that started with elevated symptomatology improved at least 1-point on CGI (79 %). Psychiatric outcomes across the cohort encompassed increased life satisfaction (17 %) and enhanced sleep quality (19 %). This pilot trial underscores the potential advantages of adjunctive ketogenic dietary treatment in individuals grappling with serious mental illness.

Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.