Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27.

The incidence of atherosclerosis is higher among patients with systemic lupus erythematosus (SLE); however, the mechanism by which an atherogenic environment affects autoimmunity remains unclear. We found that reconstitution of atherosclerosis-prone Apoe-/- and Ldlr-/- mice with bone marrow from lupus-prone BXD2 mice resulted in increased autoantibody production and glomerulonephritis. This enhanced disease was associated with an increase in CXCR3+ follicular helper T cells (TFH cells). TFH cells isolated from Apoe-/- mice had higher expression of genes associated with inflammatory responses and SLE and were more potent in inducing production of the immunoglobulin IgG2c. Mechanistically, the atherogenic environment induced the cytokine IL-27 from dendritic cells in a Toll-like receptor 4 (TLR4)-dependent manner, which in turn triggered the differentiation of CXCR3+ TFH cells while inhibiting the differentiation of follicular regulatory T cells. Blockade of IL-27 signals diminished the increased TFH cell responses in atherogenic mice. Thus, atherogenic dyslipidemia augments autoimmune TFH cell responses and subsequent IgG2c production in a TLR4- and IL-27-dependent manner.

GLP-1-directed NMDA receptor antagonism for obesity treatment.

The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.

Insulin-regulated serine and lipid metabolism drive peripheral neuropathy.

Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves1,2. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia3-7, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes8-10. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome10-14, but the mechanistic drivers and downstream consequences of this metabotype remain unclear. Low systemic serine and glycine are also emerging as a hallmark of macular and peripheral nerve disorders, correlating with impaired visual acuity and peripheral neuropathy15,16. Here we demonstrate that aberrant serine homeostasis drives serine and glycine deficiencies in diabetic mice, which can be diagnosed with a serine tolerance test that quantifies serine uptake and disposal. Mimicking these metabolic alterations in young mice by dietary serine or glycine restriction together with high fat intake markedly accelerates the onset of small fibre neuropathy while reducing adiposity. Normalization of serine by dietary supplementation and mitigation of dyslipidaemia with myriocin both alleviate neuropathy in diabetic mice, linking serine-associated peripheral neuropathy to sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidaemia as novel risk factors for peripheral neuropathy that may be exploited therapeutically.

Lipodistrophy: a paradigm for understanding the consequences of "overloading" adipose tissue.

Lipodystrophies have been recognized since at least the nineteenth century and, despite their rarity, tended to attract considerable medical attention because of the severity and somewhat paradoxical nature of the associated metabolic disease that so closely mimics that of obesity. Within the last 20 yr most of the monogenic subtypes have been characterized, facilitating family genetic screening and earlier disease detection as well as providing important insights into adipocyte biology and the systemic consequences of impaired adipocyte function. Even more recently, compelling genetic studies have suggested that subtle partial lipodystrophy is likely to be a major factor in prevalent insulin-resistant type 2 diabetes mellitus (T2DM), justifying the longstanding interest in these disorders. This progress has also underpinned novel approaches to treatment that, in at least some patients, can be of considerable therapeutic benefit.

Post-translational control of beige fat biogenesis by PRDM16 stabilization.

Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases1,2. PR domain-containing 16 (PRDM16) is a dominant activator of the biogenesis of beige adipocytes by forming a complex with transcriptional and epigenetic factors and is therefore an attractive target for improving metabolic health3-8. However, a lack of knowledge surrounding the regulation of PRDM16 protein expression hampered us from selectively targeting this transcriptional pathway. Here we identify CUL2-APPBP2 as the ubiquitin E3 ligase that determines PRDM16 protein stability by catalysing its polyubiquitination. Inhibition of CUL2-APPBP2 sufficiently extended the half-life of PRDM16 protein and promoted beige adipocyte biogenesis. By contrast, elevated CUL2-APPBP2 expression was found in aged adipose tissues and repressed adipocyte thermogenesis by degrading PRDM16 protein. Importantly, extended PRDM16 protein stability by adipocyte-specific deletion of CUL2-APPBP2 counteracted diet-induced obesity, glucose intolerance, insulin resistance and dyslipidaemia in mice. These results offer a cell-autonomous route to selectively activate the PRDM16 pathway in adipose tissues.

Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances.

BACKGROUND: Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort. METHODS: Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data. RESULTS: Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2×10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6×10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia. CONCLUSIONS: Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.

Perfluoroalkyl/Polyfluoroalkyl Substances: Links to Cardiovascular Disease Risk.

Conservative estimates by the World Health Organization suggest that at least a quarter of global cardiovascular diseases are attributable to environmental exposures. Associations between air pollution and cardiovascular risk have garnered the most headlines and are strong, but less attention has been paid to other omnipresent toxicants in our ecosystem. Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are man-made chemicals that are extensively used in industrial and consumer products worldwide and in aqueous film-forming foam utilized in firefighting. As such, our exposure to PFAS is essentially ubiquitous. Given the long half-lives of these degradation-resistant chemicals, virtually, all people are carrying a body burden of PFAS. Health concerns related to PFAS are growing such that the National Academies of Sciences, Engineering and Medicine has recommended standards for clinical follow-up of individuals with high PFAS blood levels, including prioritizing screening for dyslipidemia. The link between PFAS and dyslipidemia has been extensively investigated, and evidence for associations is compelling. However, dyslipidemia is not the only cardiovascular risk factor with which PFAS is associated. Here, we review the epidemiological evidence for links between PFAS of concern identified by the National Academies of Sciences, Engineering and Medicine and risk factors for cardiovascular disease, including overweight/obesity, glucose intolerance, hypertension, dyslipidemia, and hyperuricemia. Moreover, we review the potential connections of PFAS with vascular disease and atherosclerosis. While observational data support associations between the National Academies of Sciences, Engineering and Medicine PFAS and selected cardiac risk factors, additional research is needed to establish causation and better understand how exposure to PFAS leads to the development of these conditions.

Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes.

BACKGROUND: Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes. METHODS: We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons. RESULTS: During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group. CONCLUSIONS: In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Role of Gut Microbiota in Statin-Associated New-Onset Diabetes-A Cross-Sectional and Prospective Analysis of the FINRISK 2002 Cohort.

BACKGROUND: Dyslipidemia is treated effectively with statins, but treatment has the potential to induce new-onset type-2 diabetes. Gut microbiota may contribute to this outcome variability. We assessed the associations of gut microbiota diversity and composition with statins. Bacterial associations with statin-associated new-onset type-2 diabetes (T2D) risk were also prospectively evaluated. METHODS: We examined shallow-shotgun-sequenced fecal samples from 5755 individuals in the FINRISK-2002 population cohort with a 17+-year-long register-based follow-up. Alpha-diversity was quantified using Shannon index and beta-diversity with Aitchison distance. Species-specific differential abundances were analyzed using general multivariate regression. Prospective associations were assessed with Cox regression. Applicable results were validated using gradient boosting. RESULTS: Statin use associated with differing taxonomic composition (R2, 0.02%; q=0.02) and 13 differentially abundant species in fully adjusted models (MaAsLin; q<0.05). The strongest positive association was with Clostridium sartagoforme (ß=0.37; SE=0.13; q=0.02) and the strongest negative association with Bacteroides cellulosilyticus (ß=-0.31; SE=0.11; q=0.02). Twenty-five microbial features had significant associations with incident T2D in statin users, of which only Bacteroides vulgatus (HR, 1.286 [1.136-1.457]; q=0.03) was consistent regardless of model adjustment. Finally, higher statin-associated T2D risk was seen with [Ruminococcus] torques (ΔHRstatins, +0.11; q=0.03), Blautia obeum (ΔHRstatins, +0.06; q=0.01), Blautia sp. KLE 1732 (ΔHRstatins, +0.05; q=0.01), and beta-diversity principal component 1 (ΔHRstatin, +0.07; q=0.03) but only when adjusting for demographic covariates. CONCLUSIONS: Statin users have compositionally differing microbiotas from nonusers. The human gut microbiota is associated with incident T2D risk in statin users and possibly has additive effects on statin-associated new-onset T2D risk.

One-Year Effects of High-Intensity Statin on Bioactive Lipids: Findings From the JUPITER Trial.

BACKGROUND: Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. METHODS: Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITERdiscovery (n=589) and JUPITERvalidation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate. RESULTS: We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features. CONCLUSIONS: Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.

Bempedoic acid: new evidence and recommendations on use.

PURPOSES OF REVIEW: Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide. Recognizing the importance of dyslipidemia treatment in the prevention of cardiovascular events has become a part of standard clinical practice. Desired values of LDL cholesterol (LDL-C) have become lower and lower in the last few decades, as evidenced by the most recent guidelines. Therefore, efforts to lower LDL cholesterol concentrations with conventional therapies and combinations of lipid-lowering therapy may not be successful in a high proportion of patients. RECENT FINDINGS: Bempedoic acid is a novel agent, first in-class ATP Citrate Lyase (ACL) inhibitor, which targets biosynthesis of the cholesterol in the liver. Considering the results of phase 3 studies, it has been approved for sole use for dyslipidemia treatment for patients who are statin-intolerant or in combination with statin-ezetimibe for those suffering from familial hypercholesterolemia or ASCVD and unable to reach targeted LDL-C values. SUMMARY: Bempedoic acid has proven beneficial for further reduction of LDL cholesterol for targeted groups of patients. It is not only efficient but also a well tolerated, affordable, and available agent whose place in lipid-lowering management is yet to be fully understood with new data collected from ongoing clinical research. In this review we suggest the place of bempedoic acid in lipid-lowering management.

The current state of apolipoprotein E in dyslipidemia.

PURPOSE OF REVIEW: Apolipoprotein E (apoE) plays a pivotal role in lipid metabolism in the peripheral circulation and in the brain. This has been recognized for decades; however, the importance of the full spectrum of variation in the APOE gene has been less investigated. This review focusses on current progresses in this field with main focus on apoE in dyslipidemia and vascular disease. RECENT FINDINGS: Whereas ε4 is the risk increasing allele for Alzheimer disease, ε2 is associated with increased risk for age-related macular degeneration. Rare functional ε2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but recent findings suggest a simultaneous high risk of age-related macular degeneration, in line with observations for the ε2 allele. SUMMARY: ApoE plays an important and well established role in dyslipidemia, vascular disease, and dementia. Recent evidence from large general population studies now also suggests that apoE is involved in age-related macular degeneration. ApoE-targeted therapeutics are being developed for multiple purposes; this heralds a promising change in the approach to disease processes involving apoE. The different risk profile for dementia and age-related macular degeneration should, however, be kept in mind when developing drugs targeting mechanisms resembling these variants.

Cardiovascular Disease Risk Factor Control in People With and Without HIV.

BACKGROUND: Management of hypertension, dyslipidemia, diabetes and other modifiable factors may mitigate the cardiovascular disease (CVD) risk in people with human immunodeficiency virus (HIV, PWH) compared with people without HIV (PWoH). METHODS: This was a retrospective cohort study of 8285 PWH and 170 517 PWoH from an integrated health system. Risk factor control was measured using a novel disease management index (DMI) accounting for amount/duration above treatment goals (0% to 100% [perfect control]), including 2 DMIs for hypertension (diastolic and systolic blood pressure), 3 for dyslipidemia (low-density lipoprotein, total cholesterol, triglycerides), and 1 for diabetes (HbA1c). CVD risk by HIV status was evaluated overall and in subgroups defined by DMIs, smoking, alcohol use, and overweight/obesity in adjusted Cox proportional hazards models. RESULTS: PWH and PWoH had similar DMIs (80%-100%) except for triglycerides (worse for PWH) and HbA1c (better for PWH). In adjusted models, PWH had an elevated risk of CVD compared with PWoH (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.07-1.31). This association was attenuated in subgroups with controlled dyslipidemia and diabetes but remained elevated for PWH with controlled hypertension or higher total cholesterol. The strongest HIV status association with CVD was seen in the subgroup with frequent unhealthy alcohol use (HR, 2.13; 95% CI, 1.04-4.34). CONCLUSIONS: Control of dyslipidemia and diabetes, but not hypertension, attenuated the HIV status association with CVD. The strong association of HIV and CVD with frequent unhealthy alcohol use suggests enhanced screening and treatment of alcohol problems in PWH is warranted.

The forecasted prevalence of comorbidities and multimorbidity in people with HIV in the United States through the year 2030: A modeling study.

BACKGROUND: Estimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. The objective of our study was to forecast the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the United States (US) through 2030. METHODS AND FINDINGS: Using the PEARL model-an agent-based simulation of PWH who have initiated ART in the US-the prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV) were forecasted through 2030. Simulations were informed by the US CDC HIV surveillance data of new HIV diagnosis and the longitudinal North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data on risk of comorbidities from 2009 to 2017. The simulated population represented 15 subgroups of PWH including Hispanic, non-Hispanic White (White), and non-Hispanic Black/African American (Black/AA) men who have sex with men (MSM), men and women with history of injection drug use and heterosexual men and women. Simulations were replicated for 200 runs and forecasted outcomes are presented as median values (95% uncertainty ranges are presented in the Supporting information). In 2020, PEARL forecasted a median population of 670,000 individuals receiving ART in the US, of whom 9% men and 4% women with history of injection drug use, 60% MSM, 8% heterosexual men, and 19% heterosexual women. Additionally, 44% were Black/AA, 32% White, and 23% Hispanic. Along with a gradual rise in population size of PWH receiving ART-reaching 908,000 individuals by 2030-PEARL forecasted a surge in prevalence of most comorbidities to 2030. Depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension decreased while dyslipidemia, diabetes, CKD, and MI increased. There was little change in prevalence of cancer and ESLD. The forecasted multimorbidity among PWH receiving ART increased from 63% in 2020 to 70% in 2030. There was heterogeneity in trends across subgroups. Among Black women with history of injection drug use in 2030 (oldest demographic subgroup with median age of 66 year), dyslipidemia, CKD, hypertension, diabetes, anxiety, and depression were most prevalent, with 92% experiencing multimorbidity. Among Black MSM in 2030 (youngest demographic subgroup with median age of 42 year), depression and CKD were highly prevalent, with 57% experiencing multimorbidity. These results are limited by the assumption that trends in new HIV diagnoses, mortality, and comorbidity risk observed in 2009 to 2017 will persist through 2030; influences occurring outside this period are not accounted for in the forecasts. CONCLUSIONS: The PEARL forecasts suggest a continued rise in comorbidity and multimorbidity prevalence to 2030, marked by heterogeneities across race/ethnicity, gender, and HIV acquisition risk subgroups. HIV clinicians must stay current on the ever-changing comorbidities-specific guidelines to provide guideline-recommended care. HIV clinical directors should ensure linkages to subspecialty care within the clinic or by referral. HIV policy decision-makers must allocate resources and support extended clinical capacity to meet the healthcare needs of people aging with HIV.

Determinants of lipid clinic referral and attendance in a multi-ethnic adult population in south London: a cross-sectional study.

BACKGROUND: Primary dyslipidaemias, including familial hypercholesterolaemia, are underdiagnosed genetic disorders that substantially increase risk for premature coronary artery disease in adults. Early identification of primary dyslipidaemias via lipid clinic referral optimises patient management and enables cascade screening of relatives. Improving the identification of primary dyslipidaemias, and understanding disparities in ascertainment and management, is an NHS priority. We aimed to assess determinants of lipid clinic referral or attendance (LCR) in ethnically diverse adults. METHODS: We did a retrospective cross-sectional study using the Lambeth DataNet containing anonymised data from 41 general practitioner (GP) practices in south London. We looked at referral data for adult patients aged 18 years and older from Jan 1, 1995, until May 14, 2018. LCR was the main outcome. We used sequential multilevel logistic regression models adjusted for practice effects to estimate the odds of LCR assessed across six ethnic groups (reference group White) and patient-level factors (demographic, socioeconomic, lifestyle, comorbidities, total cholesterol [TC] >7·5mmol/L, statin prescription, and practice factors). The study was approved by NHS South East London Clinical Commissioning Group (CCG) and NHS Lambeth CCG. FINDINGS: 780 (0·23%) of 332 357 adult patients were coded as referred (n=538) or seen (n=252) in a lipid clinic. 164 487 (46·49%) were women (appendix). The fully adjusted model for odds of LCR showed the following significant associations for age (odds ratio [OR] 0·96, 95% CI 0·96-0·97, p<0·001); Black, African, Caribbean, or Black-British ethnicity (0·67, 0·53-0·84, p=0·001); ex-smoker status (1·29, 1·05-1·57, p=0·014); TC higher than 7·5 mmol/L (12·18, 9·60-15·45, p<0·001); statin prescription (14·01, 10·85-18·10, p<0·001); diabetes (0·72, 0·58-0·91, p=0·005); high-frequency GP attendance at seven or more GP consultations in the past year (1·49, 1·21-1·84, p<0·001); high GP-density (0·5-0·99 full-time equivalent GPs per 1000 patients; 2·70, 1·23-5·92, p=0·013). Sensitivity analyses for LCR restricted to familial hypercholesterolaemia-coded patients (n=581) found associations with TC higher than 7·5 mmol/L (4·26, 1·89-9·62, p<0·001), statin prescription (16·96, 2·19-131·36, p=0·007), and high GP-density (5·73, 1·27-25·93, p=0·023), with no significant associations with ethnicity. The relative contribution of GP practices to LCR was 6·32% of the total variance. There were no significant interactions between ethnicity and deprivation, age, or obesity. INTERPRETATION: While interpretation is limited by the accuracy and completeness of coded records, the study showed factors associated with a higher likelihood of LCR included individuals recorded as having TC higher than 7·5 mmol/L, statin prescription, ex-smoker status, high-frequency GP attendance, and registration at a GP practice with 0·5-0·99 GP density. Patients with increasing age; Black, African, Caribbean, or Black-British ethnicity patients; and patients with diabetes had lower odds of LCR. Finally, the difference in odds of LCR between Black and White patients highlights potential health inequalities. FUNDING: NHS Race & Health Observatory.

Long-Term Complications in Youth-Onset Type 2 Diabetes.

BACKGROUND: The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood. METHODS: We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated. RESULTS: At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up. CONCLUSIONS: Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.).

Antimullerian Hormone, a Marker of Ovarian Reserve, Is Protective Against Presence and Severity of NASH in Premenopausal Women.

BACKGROUND & AIMS: Antimüllerian hormone (AMH) is a marker of ovarian reserve with emerging data linking lower levels to some metabolic and inflammatory diseases in women. Whether AMH levels influence nonalcoholic fatty liver disease (NAFLD) is unknown. METHODS: Leveraging the NASH Clinical Research Network we determined the association of AMH levels within 6 months of liver biopsy with presence and severity of histologic measures of NAFLD in premenopausal women. Outcomes included presence of nonalcoholic steatohepatitis (NASH), presence and severity of fibrosis, and NAFLD Activity Score and its components. Logistic and ordinal logistic regression models were adjusted for age, race/ethnicity, homeostatic model assessment for insulin resistance, body mass index, dyslipidemia, polycystic ovary syndrome, estrogen-progestin use, and menstrual cyclicity. RESULTS: Median cohort age was 35 years; 73% were white and 24% Hispanic. Thirty-three percent had diabetes, 81% had obesity, and 95% had dyslipidemia. On biopsy 71% had NASH, 68% had any fibrosis, and 15% had advanced fibrosis. On adjusted analysis (n = 205), higher AMH quartiles were inversely associated with NAFLD histology including prevalent NASH (adjusted odds ratio [AOR], 0.64; 95% confidence interval [CI], 0.41-1.00), NAFLD Activity Score ≥5 (AOR, 0.52; 95% CI, 0.35-0.77), Mallory hyaline (AOR, 0.54; 95% CI, 0.35-0.82), and higher fibrosis stage (AOR, 0.70; 95% CI, 0.51-0.98). The protective effects of AMH were more pronounced among women without polycystic ovary syndrome (n = 164), including lower odds of NASH (AOR, 0.53; 95% CI, 0.32-0.90) and any NASH fibrosis (AOR, 0.54; 95% CI, 0.32-0.93). CONCLUSIONS: AMH may reflect a unique biomarker of NASH in premenopausal women and findings suggest a novel link between reproductive aging and histologic severity of NAFLD in women.

Prevalence of Liver Steatosis and Fibrosis in the General Population and Various High-Risk Populations: A Nationwide Study With 5.7 Million Adults in China.

BACKGROUND & AIMS: This study aimed to estimate the prevalence of liver steatosis and fibrosis in the general population and populations with potential risk factors in China, so as to inform policies for the screening and management of fatty liver disease and liver fibrosis in general and high-risk populations. METHODS: This cross-sectional, population-based, nationwide study was based on the database of the largest health check-up chain in China. Adults from 30 provinces who underwent a check-up between 2017 and 2022 were included. Steatosis and fibrosis were assessed and graded by transient elastography. Overall and stratified prevalence was estimated among the general population and various subpopulations with demographic, cardiovascular, and chronic liver disease risk factors. A mixed effect regression model was used to examine predictors independently associated with steatosis and fibrosis. RESULTS: In 5,757,335 participants, the prevalence of steatosis, severe steatosis, advanced fibrosis, and cirrhosis was 44.39%, 10.57%, 2.85%, and 0.87%, respectively. Participants who were male, with obesity, diabetes, hypertension, dyslipidemia, metabolic syndrome, or elevated alanine aminotransferase or aspartate aminotransferase had a significantly higher prevalence of all grades of steatosis and fibrosis, and those with fatty liver, decreased albumin or platelet count, and hepatitis B virus infection also had a significantly higher prevalence of fibrosis than their healthy counterparts. Most cardiovascular and chronic liver disease risk factors were independent predictors for steatosis and fibrosis, except for dyslipidemia for fibrosis. CONCLUSIONS: A substantial burden of liver steatosis and fibrosis was found in China. Our study provides evidence for shaping future pathways for screening and risk stratification of liver steatosis and fibrosis in the general population. The findings of this study highlight that fatty liver and liver fibrosis should be included in disease management programs as targets for screening and regular monitoring in high-risk populations, especially in those with diabetes.

Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice.

Atherosclerosis is a chronic inflammatory disease for which hepatic steatosis and atherogenic dyslipidemia are significant risk factors. We investigated the effects of endogenously generated very-long-chain polyunsaturated fatty acids (VL-PUFAs) on dyslipidemia and atherosclerosis development using mice that lack ELOVL5, a PUFA elongase that is required for the synthesis of arachidonic acid, EPA, and DHA from the essential fatty acids linoleic and linolenic acids, and the LDL receptor (LDLR). Elovl5-/-;Ldlr-/- mice manifest increased liver triglyceride and cholesterol concentrations due to the activation of sterol regulatory element binding protein-1, a transcription factor that activates enzymes required for de novo lipogenesis. Plasma levels of triglycerides and cholesterol in VLDL, IDL, and LDL were markedly elevated in Elovl5-/-;Ldlr-/- mice fed a chow and the mice exhibited marked aortic atherosclerotic plaques. Bone marrow-derived monocytes from wild-type (WT) and Elovl5-/- mice were polarized to M1 and M2 macrophages, and the effects of ELOVL5 on inflammatory activity were determined. There were no differences in most of the markers tested for M1 and M2 polarized cells between WT and Elovl5-/- cells, except for a slight increase in PGE2 secretion in Elovl5-/- cells, likely due to elevated Cox-2 expression. These results suggest that the deletion of Elovl5 leads to hepatic steatosis and dyslipidemia, which are the major factors in severe atherosclerosis in Elovl5-/-;Ldlr-/- mice.

Investigating the nexus of metabolic syndrome, serum uric acid, and dementia risk: a prospective cohort study.

BACKGROUND: The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. METHODS: Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. RESULTS: Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19-1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51-2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 µmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02-1.21; VD: HR = 1.50, 95% CI = 1.28-1.77). CONCLUSIONS: Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.