Monoclonal Antibody chP3R99 Reduces Subendothelial Retention of Atherogenic Lipoproteins in Insulin-Resistant Rats: Acute Treatment Versus Long-Term Protection as an Idiotypic Vaccine for Atherosclerosis.

BACKGROUND: Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported antiatherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans. METHODS AND RESULTS: Solid-phase assays demonstrated that chP3R99 effectively blocked >50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The preperfusion of chP3R99 (competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA-cp rats. This competitive reduction was dose dependent (25-250 µg/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a 5-week vaccination study in insulin resistant rats with (200 µg subcutaneously, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of antichondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA-cp rats. CONCLUSIONS: Both acute (passive) and long-term administration (idiotypic cascade) of chP3R99 antibody reduced low-density lipoprotein and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting proatherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis.

Predictive utility of remnant cholesterol in atherosclerotic cardiovascular disease.

PURPOSE OF REVIEW: Remnant cholesterol (RC) is the cholesterol carried in lipoproteins derived from the catabolism of chylomicrons and very low-density lipoproteins. Evidence supporting the causal relationship of RC with atherosclerotic cardiovascular disease (ASVD) is accumulating rapidly. The number of impactful contributions to this field are increasing and provide a pathophysiological insight into the current residual cardiovascular risk beyond low-density cholesterol (LDL)-cholesterol (LDL-C). They also raise the question of whether RC should be used in prediction models and become the target of new therapeutic interventions. The intent of this review is to highlight the recent advances on the role of RC in atherogenesis and the validation of RC as a predictor of ASVD. RECENT FINDINGS: Numerous prospective and retrospective cohorts helped validate a significant causal relationship of RC with various forms of ASVD, independent of LDL-C. A recent large Mendelian randomization study reinforced the existence of this relationship and showed that the risk of atherosclerotic events was driven nearly entirely by a direct effect of RC. SUMMARY: Both available and accumulating evidence suggest that a lifelong reduction in RC could translate into a substantial reduction in ASVD risk. The data support a revision of current guidelines to incorporate RC as an independent risk factor for ASVD. We propose that early screening of RC should be implemented and that RC lowering should become the target of future drug developments.

Increased Prevalence of Adverse Health Outcomes Across the Lifespan in Those Affected by Polycystic Ovary Syndrome: A Canadian Population Cohort.

Background: Polycystic ovary syndrome (PCOS) is the most common metabolic-endocrine disorder impacting the health and quality of life of women over the lifespan. Evidence-based data on the scope of adverse health outcomes in those affected by PCOS is critical to improve healthcare and quality of life in this population. The aim of this study was to determine the prevalence of adverse health outcomes in those with PCOS compared to age-matched controls. Methods: We conducted a retrospective observational case-control study in those diagnosed with PCOS and age-matched controls using the Alberta Health Services Health Analytics database and the International Classification of Diseases, for the period from 2002-2018 in Alberta, Canada. Results: The cohort consisted of n = 16,531 exposed PCOS cases and n = 49,335 age-matched un-exposed controls. The prevalences of hypertension, renal disease, gastrointestinal disease, eating disorders, mental illness, depression-anxiety, rheumatoid arthritis, respiratory infections, and all malignancies were 20%-40% (P < 0.0001) higher in those with PCOS, compared to controls. The prevalence of obesity, dyslipidemia, nonalcoholic fatty liver disease, and type 2 diabetes was 2-3 fold higher in those with PCOS (P < 0.001). Cardiovascular, cerebrovascular, and peripheral vascular disease were 30%-50% higher, and they occurred 3-4 years earlier in those with PCOS (P < 0.0001); a 2-fold higher prevalence of dementia occurred in those with PCOS, compared to controls. Conclusion: These findings provide evidence that PCOS is associated with a higher prevalence of morbidities over the lifespan, and the potential scope of the healthcare burden in women affected by PCOS.

Contexte: Le syndrome des ovaires polykystiques (SOPK) est le trouble métabolique et endocrinien le plus courant à toucher la santé et la qualité de vie des femmes de tout âge. Il est essentiel de disposer de données probantes sur l'ampleur des effets néfastes sur la santé des personnes qui en sont atteintes afin d'améliorer les soins de santé offerts à cette population et sa qualité de vie. Le but de la présente étude était de déterminer la prévalence des effets néfastes sur la santé des personnes atteintes du SOPK et de les comparer aux effets chez des témoins appariés selon l'âge. Méthodologie: Nous avons mené une étude cas-témoin observationnelle rétrospective chez des personnes diagnostiquées avec un SOPK et des témoins appariés selon l'âge en utilisant la base des données analytiques de santé de l'Alberta Health Services et la classification internationale des maladies pour l'Alberta (Canada) de 2002 à 2018. Résultats: La cohorte à l'étude était composée de cas de SOPK (n = 16 531) et de témoins appariés selon l'âge qui n'y étaient pas exposés (n = 49 335). L'hypertension, les maladies rénales, les maladies gastro-intestinales, les troubles alimentaires, les troubles de santé mentale, la dépression et l'anxiété, la polyarthrite rhumatoïde, les infections respiratoires, et les cancers de tout type étaient de 20 % à 40 % plus fréquents (p < 0,0001) chez les personnes atteintes de SOPK que chez les témoins. La prévalence de l'obésité, de la dyslipidémie, de la stéatose hépatique non alcoolique et du diabète de type 2 était 2 à 3 fois plus élevée chez les personnes atteintes de SOPK (p < 0,001). L'incidence des maladies cardiovasculaires, vasculaires cérébrales et vasculaires périphériques était 30 % à 50 % plus élevée et ces maladies survenaient 3 à 4 ans plus tôt chez les personnes atteintes de SOPK (p < 0,0001), et la prévalence de démence était 2 fois plus élevée chez les personnes atteintes de SOPK que chez les témoins. Conclusions: Ces résultats démontrent que le SOPK est associé à une prévalence plus élevée de morbidité tout au long de la vie et démontrent l'ampleur possible du fardeau en soins de santé chez les femmes touchées par le SOPK.

Prevalence and Etiology of Eating Disorders in Polycystic Ovary Syndrome: A Scoping Review.

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder affecting females across the lifespan. Eating disorders (EDs) are psychiatric conditions that may impact the development of PCOS and comorbidities including obesity, metabolic syndrome, and type 2 diabetes. The aim of this scoping review was to determine the prevalence of EDs and disordered eating, and to review the etiology of EDs in PCOS. The review was conducted using search terms addressing PCOS, EDs, and disordered eating in databases, including PubMed, Scopus, PsycINFO, and CINAHL. Structured interviews, self-administered questionnaires, chart review, or self-reported diagnosis were used to identify EDs in 38 studies included in the review. The prevalence of any ED in those with PCOS ranged from 0% to 62%. Those with PCOS were 3-6-fold more likely to have an ED and higher odds ratios (ORs) of an elevated ED score compared with controls. In those with PCOS, 30% had a higher OR of bulimia nervosa and binge ED was 3-fold higher compared with controls. Studies were limited on anorexia nervosa and other specified feeding or ED (such as night eating syndrome) and these were not reported to be higher in PCOS. To our knowledge, no studies reported on avoidant/restrictive food intake disorder, rumination disorder, or pica in PCOS. Studies showed strong associations between overweight, body dissatisfaction, and disordered eating in PCOS. The etiologic development of EDs in PCOS remains unclear; however, psychological, metabolic, hypothalamic, and genetic factors are implicated. The prevalence of any ED in PCOS varied because of the use of different diagnostic and screening tools. Screening of all individuals with PCOS for EDs is recommended and high-quality studies on the prevalence, pathogenesis of specific EDs, relationship to comorbidities, and effective interventions to treat ED in those with PCOS are needed.

Sex differences in systemic inflammation and immune function in diet-induced obesity rodent models: A systematic review.

Understanding sex differences in immunological responses in the context of obesity is important to improve health outcomes. This systematic review aimed to investigate sex differences in systemic inflammation, immune cell phenotype, and function in diet-induced obesity (DIO) animal models. A systematic search in Medline, Embase, and CINAHL from inception to April 2023 was conducted, using a combination of the following concepts: sex, obesity, cytokines, and immune cell phenotypes/function. Forty-one publications reporting on systemic inflammation (61%), cell phenotype (44%), and/or function (7%) were included. Females had lower systemic inflammation compared with males in response to DIO intervention and a higher proportion of macrophage (M)2-like cells compared with males that had a higher proportion of M1-like in adipose tissue. Although there were no clear sex differences in immune function, high-fat DIO intervention remains an important factor in the development of immune dysfunction in both males and females, including disturbances in cytokine production, proliferation, and migration of immune cells. Yet, the mechanistic links between diet and obesity on such immune dysfunction remain unclear. Future studies should investigate the role of diet and obesity in the functionality of immune cells and employ adequate methods for a high-quality investigation of sex differences in this context.

Challenges in diagnosis and health care in polycystic ovary syndrome in Canada: a patient view to improve health care.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is the most common endocrine-metabolic disorder affecting health and quality of life of those affected across the lifespan. We currently have limited evidence-based data on the experience of those living with PCOS in the health care system including diagnosis, health concerns and disease management. The aim of this study was to assess the perceptions of health status, health care experience and disease management support in those affected by PCOS in Alberta, Canada. METHODS: An online questionnaire was completed via REDCap by individuals self-reporting a diagnosis of PCOS. Question categories included demographics, symptoms of PCOS and time to confirm a diagnosis, follow-up care, health concerns, and information resources. Descriptive statistics were used and thematic analyses was applied to open-response questions. RESULTS: Responses from 194 participants living in Canada (93% in Alberta) were included. The average age was 34 ± 8 years and BMI was 35 ± 9. Menstrual irregularity was identified in 84% of respondents as the first symptom noticed and the primary reason for seeking a medical consultation. A PCOS diagnosis occurred on average 4.3 years following awareness of first symptoms and required consultation with more than one primary care provider for 57% of respondents. Half (53%) of respondents reported not receiving a referral to specialists for follow-up care and 70% were not informed about long-term health morbidity such as diabetes or cardiovascular disease. Most respondents (82%) did their own research about PCOS using on-line sources, academic literature and advice from peer support. The participant themes from open questions for improving health care included more resources and support, increased and reliable information, better education and training for clinicians, timely diagnosis, prompt referrals to specialists, and generally more compassion and empathy to the challenges faced by those managing their disease. CONCLUSION: Our findings highlight the health concerns and challenges in health care for those with PCOS. In Alberta, Canada we have identified major gaps in health care including a timely diagnosis, follow up care and supports, and multidisciplinary care. This evidence-based data can be used to inform development of pathways to improve the health care experience in those affected by PCOS.

Independent Causal Effect of Remnant Cholesterol on Atherosclerotic Cardiovascular Outcomes: A Mendelian Randomization Study.

BACKGROUND: Observational studies suggested that residual risk of cardiovascular events after LDL (low-density lipoprotein) cholesterol lowering may be linked to remnant cholesterol (RC). We conducted a large-scale Mendelian randomization study to investigate the causal role of RC to predict coronary artery disease (CAD), myocardial infarction (MI), and stroke risk. METHODS: We extracted single-nucleotide polymorphisms for RC and LDL from large-scale genome-wide association databases. We estimated the genetic association with outcomes from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics), the Metastroke consortium, as well as the GLGC (Global Lipids Genetics Consortium). Genetic variants were used as instruments, thereby minimizing residual confounding and reverse causation biases of observational studies. RESULTS: By leveraging data from a combined sample of 958 434 participants, we found evidence for a significant causal effect of RC on the risk of CAD (odds ratio [OR], 1.51 per SD unit increase in RC [95% CI, 1.42-1.60]; P=5.3×10-5), MI (OR, 1.57 [95% CI, 1.21-2.05]; P=9.5×10-4), and stroke (OR, 1.23 [95% CI, 1.12-1.35]; P=3.72×10-6). There was no evidence of pleiotropy. The effect of RC on CAD and MI remained consistent after accounting for the effects of RC-associated genetic variants on LDL cholesterol: OR, 1.49 (95% CI, 1.37-1.61) for CAD and OR, 1.80 (95% CI, 1.70-19.1) for MI without a meaningful indirect effect exerted on these outcomes via the LDL cholesterol mediator. CONCLUSIONS: This large-scale Mendelian randomization study showed a robust genetic causal association between RC and cardiovascular outcomes. The effect on CAD and MI is independent of LDL cholesterol. Early screening for RC along with long-term inhibition of RC should be the focus of future therapeutic interventions.

Sex Differences Distinctly Impact High-Fat Diet-Induced Immune Dysfunction in Wistar Rats.

BACKGROUND: Immune function is altered during obesity. Moreover, males and females across different species demonstrate distinct susceptibility to several diseases. However, less is known regarding the interplay between high-fat diet (HFD) and sex in the context of immune function. OBJECTIVES: The objective was to determine sex differences on immune function in response to an HFD compared with a control low-fat diet (LFD) in Wistar rats. METHODS: At 5 wk of age, male and female Wistar rats were randomly assigned to 1 of 2 diets for 9 wk: ad libitum control LFD (20 kcal% fat, 53 kcal% carbohydrate, and 27 kcal% protein) or HFD (50 kcal% fat, 23 kcal% carbohydrate, and 27 kcal% protein). At 13 wk of age, rats were killed and splenocytes were isolated. Immune cell subsets were determined by flow cytometry. Immune cell function was determined by measuring the ex vivo cytokine production following stimulation with mitogens. Two-factor ANOVA was used to assess the main effect of sex, diet, and their interaction. RESULTS: Males gained more weight than females (410 ± 46 vs. 219 ± 45 g), independently of diet (P-sex < 0.01). The HFD led to a lower production of IL-2 while increasing the production of IL-10 (both P-diet ≤ 0.05), independently of sex. HFD-fed females had increased production of cytokines (IL-2 and IL-6) after stimulation with phorbol 12-myristate 13-acetate plus ionomycin (PMA+I), as well as a higher T-helper (Th) 1:Th2 balance compared with HFD-fed males (all P < 0.05). Males fed the HFD had significantly lower production of IL-2 upon stimulation compared with all other groups. CONCLUSIONS: Female Wistar rats developed a milder obesity phenotype and maintained enhanced cytokine production compared with males fed the HFD. Sex differences modulate immune function in the context of high-fat feeding and it should be considered in research design to establish personalized health-related recommendations.

A Pilot Trial: Fish Oil and Metformin Effects on ApoB-Remnants and Triglycerides in Women With Polycystic Ovary Syndrome.

CONTEXT: Women with polycystic ovary syndrome (PCOS) have increased incidence of atherogenic dyslipidemia and cardiovascular disease (CVD). Interventions targeting atherogenic dyslipidemia to reduce CVD risk are limited in women with PCOS. OBJECTIVE: This pilot study was conducted to determine the effect of 12 weeks of high dose fish oil (FO), metformin, and FO as an adjunct to metformin (FO-metformin) therapy on fasting and nonfasting plasma lipids and ApoB-remnants in young women with the metabolic syndrome (MetS) and PCOS. METHODS: In this open-label parallel pilot trial, women with MetS and PCOS (18-30 years of age) were randomized into 1 of 3 interventions: (1) FO; (2) metformin; and (3) FO-metformin. Plasma lipids and ApoB (48 and 100)-lipoproteins and triglycerides (TG) were measured in the fasted and postprandial state following a high-fat meal at baseline and postintervention. RESULTS: FO-metformin significantly lowered fasting plasma TG by >40% compared with FO and metformin treatments. Fasting plasma apoB48 was lowered 40% in FO-metformin and 15% in the FO groups from baseline to postintervention. ApoB48 area under the curve (ApoB48AUC), ApoB48 incremental AUC (ApoB48iAUC), ApoB100AUC, and ApoB100iAUC decreased in all groups from baseline to postintervention; however, these findings did not reach statistical significance. CONCLUSION: The findings of this pilot trial show that high dose FO and FO-metformin combination therapy tend to lower fasting and postprandial plasma TG and ApoB-lipoprotein remnants compared with metformin; however, the study is limited by small sample size. These results may be clinically significant in individuals with PCOS for management of atherogenic dyslipidemia.

ApoB-lipoprotein remnant dyslipidemia and high-fat meal intolerance is associated with markers of cardiometabolic risk in youth with obesity.

INTRODUCTION: Cardiovascular disease (CVD) originates in childhood and risk is exacerbated in obesity. Mechanisms of the etiologic link between early adiposity and CVD-risk remain unclear. Postprandial or non-fasting dyslipidemia is characterized by elevated plasma triglycerides (TG) and intestinal-apolipoprotein(apo)B48-remnants following a high-fat meal and is a known CVD-risk factor in adults. The aim of this study was to determine (a) whether the fasting concentration of apoB48-remnants can predict impaired non-fasting apoB48-lipoprotein metabolism (fat intolerance) and (b) the relationship of these biomarkers with cardiometabolic risk factors in youth with or without obesity. METHODS: We assessed fasting and non-fasting lipids in youth without obesity (n = 22, 10 males, 12 females) and youth with obesity (n = 13, 5 males, 8 females) with a mean BMI Z-score of 0.19 ± 0.70 and 2.25 ± 0.31 (P = .04), respectively. RESULTS: Fasting and non-fasting apoB48-remnants were elevated in youth with obesity compared to youth without obesity (apoB48: 18.04 ± 1.96 vs 8.09 ± 0.59, P < .0001, and apoB48AUC : 173.0 ± 20.86 vs 61.99 ± 3.44, P < .001). Furthermore, fasting plasma apoB48-remnants were positively correlated with the non-fasting response in apoB48AUC (r = 0.84, P < .0001) as well as other cardiometabolic risk factors including HOMA-IR (r = 0.61, P < .001) and leptin (r = 0.56, P < .0001). CONCLUSION: Fasting apoB48-remnants are elevated in youth with obesity and predict apoB48 postprandial dyslipidemia. ApoB48-remnants are associated with the extent of fat intolerance and appear to be potential biomarker of CVD-risk in youth.

ApoB48-Lipoproteins Are Associated with Cardiometabolic Risk in Adolescents with and without Polycystic Ovary Syndrome.

CONTEXT: Adolescents with polycystic ovary syndrome (PCOS) have increased incidence of cardiometabolic risk factors including dyslipidemia. Atherogenic apolipoprotein (apo) B-lipoprotein remnants are associated with increased cardiovascular disease (CVD) risk. OBJECTIVE: The aim of this study was to determine the concentrations of fasting plasma apoB-lipoprotein remnants, apoB48 and apoB100, and their association with cardiometabolic risk factors and androgen indices in adolescent girls with and without PCOS. DESIGN SETTING AND PARTICIPANTS: Participants (n = 184) aged 17 years were recruited in the Menstruation in Teenagers Study from the Western Australian Pregnancy Cohort (Raine) Study. THE MAIN OUTCOME MEASURES: Fasting plasma apo-B48 and -B100 lipoprotein remnant concentrations in adolescent girls with and without PCOS. RESULTS: Fasting plasma apoB48-lipoprotein remnants but not apoB100-lipoprotein remnants were elevated in adolescent girls with increased cardiometabolic risk compared with those with lower cardiometabolic risk (13.91 ± 5.06 vs 12.09 ± 4.47 µg/mL, P < .01). ApoB48-lipoprotein remnants were positively correlated with fasting plasma triglycerides (b = .43, P < .0001). The prevalence of increased cardiometabolic risk factors was 2-fold higher in those diagnosed with PCOS (35.3%) than in those without PCOS (16.3%).Conclusion: Adolescents with PCOS have a 2-fold higher incidence of cardiometabolic risk factors than those without PCOS. Fasting apoB48-lipoprotein remnants are elevated in adolescent girls with a high prevalence of cardiometabolic risk factors.

ApoB48-remnant lipoproteins are associated with increased cardiometabolic risk in adolescents.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) begins in youth, and is exacerbated by obesity and metabolic syndrome. Apolipoprotein (Apo)B-remnant cholesterol is considered a primary contributor to CVD risk. Fasting plasma apoB48 can be used as a biomarker of intestinal remnant cholesterol as well as postprandial dyslipidemia. In adults, elevated fasting plasma apoB48 strongly associates with cardiometabolic risk factors and obesity, whereas in adolescents there is limited data. The aim of this study was to measure fasting plasma apoB48 and determine the relationship with cardiometabolic risk factors in adolescents. METHODS: This is a cross-sectional study of fasting plasma apoB48 from the Western Australian Pregnancy Cohort (Raine) Study. Subjects were adolescent males and females aged 17 years with complete fasting plasma apoB48, biochemical, and anthropometry data (n = 1045). The relationship between fasting plasma apoB48 and other cardiometabolic risk factors was determined. The high-risk metabolic cluster variable was defined using elevated BMI, HOMA-IR, fasting plasma triglycerides, and systolic blood pressure. RESULTS: Fasting plasma apoB48 was significantly higher in male (15.28 ± 2.95 µg/mL) compared to female (12.45 ± 2.43 µg/mL) adolescents (p = 0.0003), and was increased by 21% (3.60 µg/mL; p = 0.0000) in the high-risk metabolic cluster group and more pronounced in males (31%, 6.15 µg/mL; p = 0.0000). Fasting plasma apoB48 was positively associated with fasting plasma triglycerides, total-cholesterol (but not LDL-C), insulin, leptin, HOMA-IR, and the anthropometric parameters, waist-circumference and skinfold-thickness. Fasting plasma apoB48 was inversely associated with fasting plasma HDL-C, and adiponectin. CONCLUSIONS: Plasma apoB48 remnant lipoproteins associate with cardiometabolic risk factors in adolescents and provide support for the screening of remnant cholesterol in youth.

Intestinal lymphatic HDL miR-223 and ApoA-I are reduced during insulin resistance and restored with niacin.

The intestine is involved in whole-body lipid and cholesterol homeostasis and secretes lipoproteins containing apolipoprotein (Apo)B48 and discrete ApoA-I into the mesenteric lymph. The lymphatic system has been proposed to have a significant role in the reverse cholesterol transport pathway associated with HDL-ApoA-I. In conditions of insulin resistance (IR), there is intestinal overproduction of chylomicrons containing ApoB48; however, there is limited data on the intestinal synthesis and secretion of HDL-ApoA-I. microRNA (miR)-223 has been shown to regulate peripheral HDL metabolism and may impact intestinal-derived HDL. Niacin (nicotinic acid; vitamin B3) is known to regulate lipid metabolism, but the role of niacin in modulating intestinal lipid and lipoprotein (ApoB48 and ApoA-I) metabolism is unknown. The aim of this study was to determine the secretion of intestinal lymphatic HDL-ApoA-I and the effect of dietary intervention with niacin on these pathways in a rodent model of IR. HDL was isolated from intestinal mesenteric lymph by density ultracentrifugation, and subsequent HDL miR analysis was developed in collaboration with Exiqon Services. Insulin-resistant rodents were fed chow or chow with niacin (1% w/w) for 6 wk. Intestinal lymph HDL-ApoA-I and miR-223 expression were lower by at least 45 and 60%, respectively, and lymph HDL was associated with 85% higher triglyceride (TG) content in IR compared to non-IR control group. Niacin was found to increase secretion of lymph HDL and miR-223 by at least 50-60% and to deplete the TGs associated with HDL compared with the nontreated IR group. Niacin significantly increased peroxisome proliferator-activating nuclear receptor α and carnitine palmitoyltransferase I α mRNA and annulled Tnf-α mRNA expression in intestinal (jejunal) explants. Altered intestinal lymphatic HDL-ApoA-I and miR-223 metabolism in IR and modulation by niacin may provide insight into the intestinal-mediated regulation of the reverse cholesterol transport pathway.-Mangat, R., Borthwick, F., Haase, T., Jacome, M., Nelson, R., Kontush, A., Vine, D. F., Proctor, S. D. Intestinal lymphatic HDL miR-223 and ApoA-I are reduced during insulin resistance and restored with niacin.

Surgical Anatomy Does Not Affect the Progression of Intestinal Failure-Associated Liver Disease in Neonatal Piglets.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) causes significant morbidity in neonates with short bowel syndrome (SBS) dependent on parenteral nutrition (PN). Resected ileum, with loss of the ileocecal valve (ICV), is the most common anatomy in SBS, yet its impact on IFALD has not been adequately studied. METHODS: Neonatal piglets were randomized to 75% intestinal resection with jejunocolic anastomosis (JC, n = 12), 75% resection with jejunoileal anastomosis and intact ICV (JI, n = 13), PN-fed sham (sham, n = 14), or sow-fed control (SF, n = 8). Surgical and sham piglets received 100% PN for 14 days before bile flow was measured and blood chemistry, liver pathology, jejunal permeability, and bacterial translocation were assessed. RESULTS: Bile flow was lower for PN-fed compared with SF (P = .002) but not different between the PN-fed groups. Total bilirubin (P = .03) and liver pathology (P < .001) were greater in PN-fed than SF groups but not different between PN-fed groups. Serum bile acids were increased in sham (P = .01) but not different between SBS groups. PN-fed piglets with sepsis had lower bile flow (P = .001) and increased bilirubin (P = .04). Neither jejunal permeability nor bacterial translocation were different between JC, JI, or sham groups. CONCLUSION: Contrary to our hypothesis, the remnant anatomy does not appear to worsen the progression of IFALD. However, the role of sepsis in IFALD should be further explored, in addition to other mechanisms, including PN factors, host immune responses, and intestinal bacterial dysbiosis.

The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB-Lipoprotein Response.

Context: Proprotein convertase subtilisin kexin 9 (PCSK9) mediates degradation of the low-density lipoprotein receptor (LDLR), thereby increasing plasma low-density lipoprotein cholesterol (LDL-C). Variations in the PCSK9 gene associated with loss of function (LOF) of PCSK9 result in greater expression of hepatic LDLR, lower concentrations of LDL-C, and protection from cardiovascular disease (CVD). Apolipoprotein-B (apoB) remnants also contribute to CVD risk and are similarly cleared by the LDLR. We hypothesized that PCSK9-LOF carriers would have lower fasting and postprandial remnant lipoproteins on top of lower LDL-C. Objective: To compare fasting and postprandial concentrations of triglycerides (TGs), total apoB, and apoB48 as indicators of remnant lipoprotein metabolism in PCSK9-LOF carriers with those with no PCSK9 variants. Design: Case-control, metabolic study. Setting: Clinical Research Center of The Ottawa Hospital. Participants: Persons with one or more copies of the L10ins/A53V and/or I474V and/or R46L PCSK9 variant and persons with no PCSK9 variants. Intervention: Oral fat tolerance test. Main Outcomes Measures: Fasting and postprandial plasma TG, apoB48, total apoB, total cholesterol, and PCSK9 were measured at 0, 2, 4, and 6 hours after an oral fat load. Results: Participants with PCSK9-LOF variants (n = 22) had reduced fasting LDL-C (-14%) as well as lower fasting TG (-21%) compared with noncarrier controls (n = 23). LOF variants also had reduced postprandial total apoB (-17%), apoB48 (-23%), and TG (-18%). Postprandial PCSK9 declined in both groups (-24% vs -16%, respectively). Conclusions: Participants carrying PCSK9-LOF variants had attenuated levels of fasting and postprandial TG, apoB48, and total apoB. This may confer protection from CVD and further validate the use of PCSK9 inhibitors to lower CVD risk.

Nutritional and Lipid Modulation of PCSK9: Effects on Cardiometabolic Risk Factors.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease involved in the regulation of LDL receptor (LDLR) expression and apolipoprotein B lipoprotein cholesterol metabolism. Hepatic PCSK9 protein expression, activity, and secretion have been shown to affect cholesterol homeostasis. An upregulation of hepatic PSCK9 protein leads to increased LDLR degradation, resulting in decreased uptake of apoB lipoproteins and a consequent increase in the plasma concentration of these lipoproteins, including LDL and chylomicron remnants. Hence, PCSK9 has become a novel target for lipid-lowering therapies. The aim of this review is to outline current findings on the metabolic and dietary regulation of PCSK9 and effects on cholesterol, apoB lipoprotein metabolism, and cardiovascular disease (CVD) risk. PCSK9 gene and protein expression have been shown to be regulated by metabolic status and the diurnal pattern. In the fasting state, plasma PCSK9 is reduced via modulation of the nuclear transcriptional factors, including sterol regulatory element-binding protein (SREBP) 1c, SREBP2, and hepatocyte nuclear factor 1α. Plasma PCSK9 concentrations are also known to be positively associated with plasma insulin and homeostasis model assessment of insulin resistance, and appear to be regulated by SREBP1c independently of glucose status. Plasma PCSK9 concentrations are stable in response to high-fat or high-protein diets in healthy individuals; however, this response may differ in altered metabolic conditions. Dietary n-3 polyunsaturated fatty acids have been shown to reduce plasma PCSK9 concentration and hepatic PCSK9 mRNA expression, consistent with their lipid-lowering effects, whereas dietary fructose appears to upregulate PCSK9 mRNA expression and plasma PCSK9 concentrations. Further studies are needed to elucidate the mechanisms of how dietary components regulate PCSK9 and effects on cholesterol and apoB lipoprotein metabolism, as well as to delineate the clinical impact of diet on PCSK9 in terms of CVD risk.

Synergy of glucagon-like peptide-2 and epidermal growth factor coadministration on intestinal adaptation in neonatal piglets with short bowel syndrome.

Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) treatment enhance intestinal adaptation. To determine whether these growth factors exert synergistic effects on intestinal growth and function, GLP-2 and EGF-containing media (EGF-cm) were administered, alone and in combination, in neonatal piglet models of short bowel syndrome (SBS). Neonatal Landrace-Large White piglets were block randomized to 75% midintestinal [jejunoileal (JI) group] or distal intestinal [jejunocolic (JC) group] resection or sham control, with 7-day infusion of saline (control), intravenous human GLP-2 (11 nmol·kg-1·day-1) alone, enteral EGF-cm (80 µg·kg-1·day-1) alone, or GLP-2 and EGF-cm in combination. Adaptation was assessed by intestinal length, histopathology, Üssing chamber analysis, and real-time quantitative PCR of intestinal growth factors. Combined EGF-cm and GLP-2 treatment increased intestinal length in all three surgical models (P < 0.01). EGF-cm alone selectively increased bowel weight per length and jejunal villus height in the JI group only. The JC group demonstrated increased intestinal weight and villus height (P < 0.01) when given either GLP-2 alone or in combination with EGF-cm, with no effect of EGF-cm alone. Jejunal permeability of mannitol and polyethylene glycol decreased with combination therapy in both SBS groups (P < 0.05). No difference was observed in fat absorption or body weight gain. IGF-1 mRNA was differentially expressed in JI vs. JC piglets with treatment. Combined treatment with GLP-2 and EGF-cm induced intestinal lengthening and decreased permeability, in addition to the trophic effects of GLP-2 alone. Our findings demonstrate the benefits of novel combination GLP-2 and EGF treatment for neonatal SBS, especially in the JC model representing most human infants with SBS.NEW & NOTEWORTHY Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) are intestinotrophic, with demonstrated benefit in both animal models and human studies of short bowel syndrome (SBS). The current research shows that over and above known trophic effects, the combination of GLP-2 and EGF synergistically lengthens the bowel in neonatal piglet models of SBS. Most notable benefit occurred with resection of the terminal ileum, the common clinical anatomy seen in neonatal SBS and associated with least de novo lengthening postsurgery.

Differential Effects on Intestinal Adaptation Following Exogenous Glucagon-Like Peptide 2 Therapy With and Without Enteral Nutrition in Neonatal Short Bowel Syndrome [Formula: see text].

BACKGROUND: We aim to study the efficacy of exogenously administered glucagon-like peptide 2 (GLP-2) on intestinal adaptation in 2 preclinical models of neonatal short bowel syndrome (SBS) according to remnant intestinal anatomy, with and without ileum. Furthermore, we aim to determine if this adaptive effect was potentiated with enteral nutrition (EN). METHODS: Neonatal piglets were block-randomized to 75% mid-intestinal (JI group, retains ileum) or distal-intestinal (JC group, has no ileum) resection or no resection (sham control) and GLP-2 treatment (11 nmol/kg/d) or saline control for 7 days. Piglets received nutrition support, either 100% parenteral nutrition (PN; 0% EN, n = 32 in total) or 80% PN + 40% EN (n = 28 in total). Adaptation was assessed by morphological and histological changes, as well as RT quantitative polymerase chain reaction of nutrient transporters and tight junctional proteins and fat absorption. Data are analyzed by 3-way analysis of variance (ANOVA) and 2-way ANOVA per EN level. RESULTS: GLP-2 treatment lengthened villi, deepened crypts, and improved intestinal weight in the remnant intestine of JC piglets. EN was a more potent adaptive stimulus for JI piglets. Small intestinal lengthening occurred only in the JI group, when given EN. There was no difference in total fat absorption and messenger RNA expression of nutrient transporters and tight junctional proteins. CONCLUSIONS: GLP-2 administration augmented structural adaptation in JC piglets with distal intestinal resection. Given JI anatomy, further stimulation by GLP-2 treatment over innate adaptation and stimulation by EN was modest and restricted to ileum. The differential effect of GLP-2 in neonatal SBS, depending on remnant anatomy, has important implications for clinical translation and planning of clinical trials.

Impaired ApoB-Lipoprotein and Triglyceride Metabolism in Obese Adolescents With Polycystic Ovary Syndrome.

CONTEXT: Adolescents with polycystic ovary syndrome (PCOS) have atherogenic dyslipidemia and increased cardiovascular disease (CVD) risk, and this is exacerbated in obesity. OBJECTIVE: To determine and compare fasting and nonfasting lipid and apolipoprotein (Apo)B-lipoprotein metabolism in 3 groups of adolescent girls: healthy-weight controls, obese without PCOS (obese-control), and obese with PCOS (obese-PCOS). DESIGN, SETTING, AND PARTICIPANTS: Participants aged 12 to 17 years were recruited for this cross-sectional study from a pediatric weight management clinic and the local community in Alberta, Canada. MAIN OUTCOME MEASURES: Plasma lipids and ApoB lipoproteins, including triglycerides (TGs) and ApoB100- and ApoB48-lipoproteins, were measured in the fasted and postprandial state following a high-fat meal. RESULTS: Obese-control (n = 12) and obese-PCOS (n = 18) groups had twofold higher concentrations of fasting plasma TG and ApoB100- and ApoB48-lipoprotein remnants compared to healthy-weight controls (n = 10) (ApoB48-lipoproteins: 19.32 ± 2.10, 24.02 ± 4.28, and 8.95 ± 1.05 µg/mL, respectively; P < 0.001). The obese-PCOS group had 50% higher fasting plasma TG level compared to the obese-control group. The postprandial response was higher in both obese-controls and obese-PCOS subjects compared with healthy-weight controls in plasma TG area under the curve (AUC) (1028.0 ± 83.67, 1587.01 ± 259.6, and 615.42 ± 76.42 µg/mL⋅h, respectively; P < 0.01) and ApoB48(AUC) (191.30 ± 19.06, 238.8 ± 37.73, and 96.58 ± 9.17 µg/mL⋅h, respectively; P < 0.0001). Nonfasting plasma TG(AUC) and ApoB48(AUC) were positively correlated with free testosterone (r = 0.38; P < 0.001 and r = 0.33; P < 0.05, respectively), and these relationships were highly associated with insulin and body mass index. CONCLUSIONS: Adolescent girls with obesity and PCOS have elevated fasting and postprandial plasma TG and ApoB-lipoprotein remnants, providing evidence of early subclinical CVD risk, and these indices are highly associated with impaired insulin metabolism and hyperandrogenemia.

Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the JCR:LA-cp Corpulent Rat Strain.

Obesity and its metabolic complications have emerged as the epidemic of the new millennia. The use of obese rodent models continues to be a productive component of efforts to understand the concomitant metabolic complications of this disease. In 1978, the JCR:LA-cp rat model was developed with an autosomal recessive corpulent (cp) trait resulting from a premature stop codon in the extracellular domain of the leptin receptor. Rats that are heterozygous for the cp trait are lean-prone, while those that are homozygous (cp/cp) spontaneously display the pathophysiology of obesity as well as a metabolic syndrome (MetS)-like phenotype. Over the years, there have been formidable scientific contributions that have originated from this rat model, much of which has been reviewed extensively up to 2008. The premise of these earlier studies focused on characterizing the pathophysiology of MetS-like phenotype that was spontaneously apparent in this model. The purpose of this review is to highlight areas of recent advancement made possible by this model including; emerging appreciation of the "thrifty gene" hypothesis in the context of obesity, the concept of how chronic inflammation may drive obesogenesis, the impact of acute forms of inflammation to the brain and periphery during chronic obesity, the role of dysfunctional insulin metabolism on lipid metabolism and vascular damage, and the mechanistic basis for altered vascular function as well as novel parallels between the human condition and the female JCR:LA-cp rat as a model for polycystic ovary disease (PCOS).