Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.

Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

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.

VLDL Biogenesis and Secretion: It Takes a Village.

The production and secretion of VLDLs (very-low-density lipoproteins) by hepatocytes has a direct impact on liver fat content, as well as the concentrations of cholesterol and triglycerides in the circulation and thus affects both liver and cardiovascular health, respectively. Importantly, insulin resistance, excess caloric intake, and lack of physical activity are associated with overproduction of VLDL, hepatic steatosis, and increased plasma levels of atherogenic lipoproteins. Cholesterol and triglycerides in remnant particles generated by VLDL lipolysis are risk factors for atherosclerotic cardiovascular disease and have garnered increasing attention over the last few decades. Presently, however, increased risk of atherosclerosis is not the only concern when considering today's cardiometabolic patients, as they often also experience hepatic steatosis, a prevalent disorder that can progress to steatohepatitis and cirrhosis. This duality of metabolic risk highlights the importance of understanding the molecular regulation of the biogenesis of VLDL, the lipoprotein that transports triglycerides and cholesterol out of the liver. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL by hepatocytes, which has led to many exciting new molecular insights that are the topic of this review. Increasing our understanding of the biology of this pathway will aid to the identification of novel therapeutic targets to improve both the cardiovascular and the hepatic health of cardiometabolic patients. This review focuses, for the first time, on this duality.

A novel fully human anti-NT-ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL-C lowering activities in hyperlipidemia mice.

Dyslipidemia is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and TG-rich lipoprotein (TGRLs) in circulation, and is closely associated with the incidence and development of cardiovascular disease. Angiopoietin-like protein 3 (ANGPTL3) deficiency has been identified as a cause of familial combined hypolipidemia in humans, which allows it to be an important therapeutic target for reducing plasma lipids. Here, we report the discovery and characterization of a novel fully human antibody F1519-D95aA against N-terminal ANGPTL3 (NT-ANGPTL3), which potently inhibits NT-ANGPTL3 with a KD as low as 9.21 nM. In hyperlipidemic mice, F1519-D95aA shows higher apolipoprotein B (ApoB) and TG-lowering, and similar LDL-C reducing activity as compared to positive control Evinacumab (56.50% vs 26.01% decrease in serum ApoB levels, 30.84% vs 25.28% decrease in serum TG levels, 23.32% vs 22.52% decrease in serum LDLC levels, relative to vehicle group). Molecular docking and binding energy calculations reveal that the F1519-D95aA-ANGPTL3 complex (10 hydrogen bonds, -65.51 kcal/mol) is more stable than the Evinacumab-ANGPTL3 complex (4 hydrogen bonds, -63.76 kcal/mol). Importantly, F1519-D95aA binds to ANGPTL3 with different residues in ANGPTL3 from Evinacumab, suggesting that F1519-D95aA may be useful for the treatment of patients resistant to Evinacumab. In conclusion, F1519-D95aA is a novel fully human anti-NT-ANGPTL3 antibody with potent plasma ApoB, TG, and LDL-C lowering activities, which can potentially serve as a therapeutic agent for hyperlipidemia and relevant cardiovascular diseases.

Ceramides in Metabolism: Key Lipotoxic Players.

The global prevalence of metabolic diseases such as type 2 diabetes mellitus, steatohepatitis, myocardial infarction, and stroke has increased dramatically over the past two decades. These obesity-fueled disorders result, in part, from the aberrant accumulation of harmful lipid metabolites in tissues not suited for lipid storage (e.g., the liver, vasculature, heart, and pancreatic beta-cells). Among the numerous lipid subtypes that accumulate, sphingolipids such as ceramides are particularly impactful, as they elicit the selective insulin resistance, dyslipidemia, and ultimately cell death that underlie nearly all metabolic disorders. This review summarizes recent findings on the regulatory pathways controlling ceramide production, the molecular mechanisms linking the lipids to these discrete pathogenic events, and exciting attempts to develop therapeutics to reduce ceramide levels to combat metabolic disease.

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.

Causal effect of severe and non-severe malaria on dyslipidemia in African Ancestry individuals: A Mendelian randomization study.

BACKGROUND: Dyslipidemia is becoming prevalent in Africa, where malaria is endemic. Observational studies have documented the long-term protective effect of malaria on dyslipidemia; however, these study designs are prone to confounding. Therefore, we used Mendelian randomization (MR, a method robust to confounders and reverse causation) to determine the causal effect of severe malaria (SM) and the recurrence of non-severe malaria (RNM) on lipid traits. METHOD: We performed two-sample MR using genome wide association study (GWAS) summary statistics for recurrent non-severe malaria (RNM) from a Benin cohort (N = 775) and severe malaria from the MalariaGEN dataset (N = 17,000) and lipid traits from summary-level data of a meta-analyzed African lipid GWAS (MALG, N = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612) and the Africa Wits-IN-DEPTH partnership for genomics studies (AWI-Gen) dataset (N = 10,603). RESULT: No evidence of significant causal association was obtained between RNM and high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol and triglycerides. However, a notable association emerged between severe malarial anaemia (SMA) which is a subtype of severe malaria and reduced HDL-C levels, suggesting a potential subtype-specific effect. Nonetheless, we strongly believe that the small sample size likely affects our estimates, warranting cautious interpretation of these results. CONCLUSION: Our findings challenge the hypothesis of a broad causal relationship between malaria (both severe and recurrent non-severe forms) and dyslipidemia. The isolated association with SMA highlights an intriguing area for future research. However, we believe that conducting larger studies to investigate the connection between malaria and dyslipidemia in Africa will enhance our ability to better address the burden posed by both diseases.

Metabolic Sequelae: The Pancreatitis Zeitgeist of the 21st Century.

Holistic management of pancreatitis means that gastroenterologists in the 21st Century should think beyond improving in-hospital outcomes of pancreatitis alone. In particular, there is considerable room for optimizing the management of new-onset diabetes, exocrine pancreatic insufficiency, and other metabolic sequelae of pancreatitis. The present article provides state-of-the-art information on classification, terminology, and burden of the common sequelae of pancreatitis. A high-risk group of patients with pancreatitis is identified, which is positioned to benefit the most from the metabolic sequelae surveillance program introduced in this article. The program involves continuous follow-up after pancreatitis diagnosis, with the focus on early identification of new-onset diabetes after pancreatitis and exocrine pancreatic insufficiency. The metabolic sequelae surveillance program is scalable and has the potential to reduce the burden of pancreatitis through tertiary prevention in the decades to come.

The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes.

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m2, and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

Haplotype analysis and linkage disequilibrium of ApoB gene polymorphisms and its relationship with hyperlipidemia in patients with acne vulgaris.

BACKGROUND: Acne vulgaris (AV) is a chronic, multifactorial inflammatory disease of the pilosebaceous unit brought on by hormonal imbalance, excessive sebum production, follicular hyperkeratinization, inflammation and Cutibacterium acne. Acne patients are characterized by alteration of the lipid profile. Apolipoprotein B gene (ApoB) plays an essential role in lipoprotein biosynthesis and multiple single-nucleotide polymorphisms (SNPs) in ApoB are associated with dyslipidemia. AIM: The aim of this study was to estimate the alteration of lipid profiles in AV, determine the genetic association with lipid profile alteration by studying the ApoB gene polymorphisms, and to identify the exact haplotypes associated with acne and lipid profile alteration. SUBJECTS AND METHODS: In a case-control study consisting of 63 non-obese acne patients and 43 healthy controls, all participants underwent biochemical, anthropological assessments, and genetic analysis for ApoB polymorphisms. RESULT: Our results indicate that serum ApoB and the lipid profile were higher in acne patients compared with healthy subject. The most common haplotypes in acne patients were rs562338 A/rs17240441 I/c.12669 A/rs1042034 G, whereas the most common haplotypes in healthy subjects were rs562338 G/rs17240441 D/c.12669 A/rs1042034 G. Patients with mild acne had higher serum ApoB levels p = 0.005. Also, the low-density lipoprotein cholesterol (LDL-C) level was higher in mild acne compared with other acne groups, with a highly significant variation of p ≤ 0.001. CONCLUSION: We found a significant variation between the acne group and healthy controls in serum ApoB, triglycerides, total cholesterol and LDL-C. The most common haplotypes in acne patients are rs562338 A/, rs17240441 I/, c.12669 A/ and rs1042034 G, and there is a linkage disequilibrium between the four selected SNPs.

Unmasking the morphological alteration of erythrocytes among women suffering from PCOS.

Dyslipidemia is frequently observed in polycystic ovarian syndrome (PCOS). Changes in plasma lipid levels potentially alter erythrocyte membrane lipid composition due to lack of inbuilt lipid synthesis machinery. Therefore, development of morphologically altered erythrocytes in PCOS patients with dyslipidemia is expected. However, this has not been established so far. So, we took this opportunity to explore the morphological alterations among dyslipidemic PCO women. We recruited thirty-five dyslipidemic PCOS women (satisfying Rotterdam criteria, without medication) and twenty-five age-matched healthy controls. Scanning electron microscopy revealed a significant increase in the number of stomatocytes, acanthocytes, and echinocytes in the PCO group. PCO group showed a considerable decrease in plasma antioxidant levels. Elevated lipid peroxidation, protein carbonylation, and decreased free thiol group in erythrocyte membrane in PCOS suggest oxidative degradation of the erythrocyte membrane. Elevated intracellular ROS levels, increased methemoglobin formation, and a decrease in NADPH methemoglobin reductase in PCOS also indicate altered physicochemical property of hemoglobin due to oxidative overload. Additionally, these patients exhibit a rise in erythrocyte membrane cholesterol and triglyceride, which promotes the membrane to become less fluidic and less fragile. Thus, these results corroborate a potential role in altering erythrocyte morphology among dyslipidemic PCO women.

Comparison of Clinical Decision Support Tools to Improve Pediatric Lipid Screening.

OBJECTIVE: To test whether different clinical decision support tools increase clinician orders and patient completions relative to standard practice and each other. STUDY DESIGN: A pragmatic, patient-randomized clinical trial in the electronic health record was conducted between October 2019 and April 2020 at Geisinger Health System in Pennsylvania, with 4 arms: care gap-a passive listing recommending screening; alert-a panel promoting and enabling lipid screen orders; both; and a standard practice-no guideline-based notification-control arm. Data were analyzed for 13 346 9- to 11-year-old patients seen within Geisinger primary care, cardiology, urgent care, or nutrition clinics, or who had an endocrinology visit. Principal outcomes were lipid screening orders by clinicians and completions by patients within 1 week of orders. RESULTS: Active (care gap and/or alert) vs control arm patients were significantly more likely (P < .05) to have lipid screening tests ordered and completed, with ORs ranging from 1.67 (95% CI 1.28-2.19) to 5.73 (95% CI 4.46-7.36) for orders and 1.54 (95% CI 1.04-2.27) to 2.90 (95% CI 2.02-4.15) for completions. Alerts, with or without care gaps listed, outperformed care gaps alone on orders, with odds ratios ranging from 2.92 (95% CI 2.32-3.66) to 3.43 (95% CI 2.73-4.29). CONCLUSIONS: Electronic alerts can increase lipid screening orders and completions, suggesting clinical decision support can improve guideline-concordant screening. The study also highlights electronic record-based patient randomization as a way to determine relative effectiveness of support tools. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04118348.

Characterization of the gut microbiota in polycystic ovary syndrome with dyslipidemia.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrinopathy in childbearing-age females which can cause many complications, such as diabetes, obesity, and dyslipidemia. The metabolic disorders in patients with PCOS were linked to gut microbial dysbiosis. However, the correlation between the gut microbial community and dyslipidemia in PCOS remains unillustrated. Our study elucidated the different gut microbiota in patients with PCOS and dyslipidemia (PCOS.D) compared to those with only PCOS and healthy women. RESULTS: In total, 18 patients with PCOS, 16 healthy females, and 18 patients with PCOS.D were enrolled. The 16 S rRNA sequencing in V3-V4 region was utilized for identifying the gut microbiota, which analyzes species annotation, community diversity, and community functions. Our results showed that the ß diversity of gut microbiota did not differ significantly among the three groups. Regarding gut microbiota dysbiosis, patients with PCOS showed a decreased abundance of Proteobacteria, and patients with PCOS.D showed an increased abundance of Bacteroidota compared to other groups. With respect to the gut microbial imbalance at genus level, the PCOS.D group showed a higher abundance of Clostridium_sensu_stricto_1 compared to other two groups. Furthermore, the abundances of Faecalibacterium and Holdemanella were lower in the PCOS.D than those in the PCOS group. Several genera, including Faecalibacterium and Holdemanella, were negatively correlated with the lipid profiles. Pseudomonas was negatively correlated with luteinizing hormone levels. Using PICRUSt analysis, the gut microbiota community functions suggested that certain metabolic pathways (e.g., amino acids, glycolysis, and lipid) were altered in PCOS.D patients as compared to those in PCOS patients. CONCLUSIONS: The gut microbiota characterizations in patients with PCOS.D differ from those in patients with PCOS and controls, and those might also be related to clinical parameters. This may have the potential to become an alternative therapy to regulate the clinical lipid levels of patients with PCOS in the future.

Metabolic effects and cardiovascular disease risks of antiviral treatments in patients with chronic hepatitis B.

Different antiviral treatments for chronic hepatitis B (CHB) have been known to have different metabolic effects. This study aimed to reveal whether tenofovir alafenamide (TAF)-induced dyslipidemia and its associated outcomes are significant. This study utilized 15-year historical cohort including patients with CHB in Korea and consisted of two parts: the single-antiviral and switch-antiviral cohorts. In the single-antiviral cohort, patients were divided into four groups (entecavir [ETV]-only, tenofovir disoproxil fumarate [TDF]-only, TAF-only, and non-antiviral). Propensity score matching (PSM) and linear regression model were sequentially applied to compare metabolic profiles and estimated atherosclerotic cardiovascular disease (ASCVD) risks longitudinally. In the switch-antiviral cohort, pairwise analyses were conducted in patients who switched NAs to TAF or from TAF. In the single-antiviral cohort, body weight and statin use showed significant differences between groups before PSM, but well-balanced after PSM. Changes in total cholesterol were significantly different between groups (-2.57 mg/dL/year in the TDF-only group and +2.88 mg/dL/year in the TAF-only group; p = 0.002 and p = 0.02, respectively). In the TDF-only group, HDL cholesterol decreased as well (-0.55 mg/dL/year; p < 0.001). The TAF-only group had the greatest increase in ASCVD risk, followed by the TDF-only group and the non-antiviral group. In the switch-antiviral cohort, patients who switched from TDF to TAF had a higher total cholesterol after switching (+9.4 mg/dL/year) than before switching (-1.0 mg/dL/year; p = 0.047). Sensitivity analysis on data with an observation period set to a maximum of 3 years for NA treatment showed consistent results on total cholesterol (-2.96 mg/dL/year in the TDF-only group and +3.09 mg/dL/year in the TAF-only group; p = 0.001 and p = 0.005, respectively). Another sensitivity analysis conducted on statin-treated patients revealed no significant change in cholesterol and ASCVD risk. TAF was associated with increased total cholesterol, whereas TDF was associated with decreased total and HDL cholesterol. Both TAF and TDF were associated with increased ASCVD risks, and statin use might mitigate these risks.

Hepatic insulin resistance and muscle insulin resistance are characterized by distinct postprandial plasma metabolite profiles: a cross-sectional study.

BACKGROUND: Tissue-specific insulin resistance (IR) predominantly in muscle (muscle IR) or liver (liver IR) has previously been linked to distinct fasting metabolite profiles, but postprandial metabolite profiles have not been investigated in tissue-specific IR yet. Given the importance of postprandial metabolic impairments in the pathophysiology of cardiometabolic diseases, we compared postprandial plasma metabolite profiles in response to a high-fat mixed meal between individuals with predominant muscle IR or liver IR. METHODS: This cross-sectional study included data from 214 women and men with BMI 25-40 kg/m2, aged 40-75 years, and with predominant muscle IR or liver IR. Tissue-specific IR was assessed using the muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI), which were calculated from the glucose and insulin responses during a 7-point oral glucose tolerance test. Plasma samples were collected before (T = 0) and after (T = 30, 60, 120, 240 min) consumption of a high-fat mixed meal and 247 metabolite measures, including lipoproteins, cholesterol, triacylglycerol (TAG), ketone bodies, and amino acids, were quantified using nuclear magnetic resonance spectroscopy. Differences in postprandial plasma metabolite iAUCs between muscle and liver IR were tested using ANCOVA with adjustment for age, sex, center, BMI, and waist-to-hip ratio. P-values were adjusted for a false discovery rate (FDR) of 0.05 using the Benjamini-Hochberg method. RESULTS: Sixty-eight postprandial metabolite iAUCs were significantly different between liver and muscle IR. Liver IR was characterized by greater plasma iAUCs of large VLDL (p = 0.004), very large VLDL (p = 0.002), and medium-sized LDL particles (p = 0.026), and by greater iAUCs of TAG in small VLDL (p = 0.025), large VLDL (p = 0.003), very large VLDL (p = 0.002), all LDL subclasses (all p < 0.05), and small HDL particles (p = 0.011), compared to muscle IR. In liver IR, the postprandial plasma fatty acid (FA) profile consisted of a higher percentage of saturated FA (p = 0.013), and a lower percentage of polyunsaturated FA (p = 0.008), compared to muscle IR. CONCLUSION: People with muscle IR or liver IR have distinct postprandial plasma metabolite profiles, with more unfavorable postprandial metabolite responses in those with liver IR compared to muscle IR.

Multi-species synbiotic supplementation increased fecal short chain fatty acids and anti-inflammatory cytokine interleukin-10 in adult men with dyslipidemia; A randomized, double-blind, clinical trial.

BACKGROUND: Mounting evidence revealed that an imbalance of Gut Microbiota (GM) leads to metabolic disorders. Synbiotics through regulation of GM composition can be an effective intervention in the management of metabolic diseases. This study aimed to investigate the effects of multi-species synbiotic supplementation on serum interleukin10 (IL-10) and fecal Short Chain Fatty Acids (SCFAs) in patients with dyslipidemia. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, fifty-six adult men with dyslipidemia were randomly allocated to intervention and control groups and received either synbiotic or placebo powder twice a day for 12 weeks. Each synbiotic sachet contained 6 species of probiotic microorganisms with a total dose of 3 × 1010 Colony Forming Unit (CFU) and 5 gr inulin and Fructooligosaccharide (FOS) as prebiotics. Blood and stool samples were collected at the baseline and end of the study. Dietary intake, physical activity, anthropometric measurements, serum IL-10, and fecal SCFAs were assessed before and after the intervention. RESULT: There were no significant differences between the baseline characteristics of patients in the two groups. Serum IL-10 was increased in the synbiotic group (p < 0.0001). Moreover, synbiotic supplementation increased fecal concentration of acetate (p < 0.0001), butyrate (p = 0.043), propionate (p < 0.0001), and valerate (p < 0.026). A significant positive correlation was observed between the changes in fecal butyrate level and serum IL-10 concentration in the control group (r = 0.48, p = 0.01). CONCLUSIONS: A Twelve-week synbiotic supplementation increased fecal SCFAs and improved inflammation in adult men with dyslipidemia.

Allergic inflammation triggers dyslipidemia via IgG signalling.

BACKGROUND: Allergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. METHODS: We used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell-depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post-allergen challenge. Also, changes in serum triglycerides (TGs) were evaluated in a group of 59 patients ≥14 days after the onset of an allergic reaction. RESULTS: We found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TGs and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T-cell-driven late phase inflammation. On the contrary, the IgG-mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TGs in 59 patients after undergoing an allergic reaction. CONCLUSION: Overall, this study reveals that IgG-mediated allergic inflammation regulates lipid metabolism.

Association of Fibroblast Growth Factor 23 with Blood Pressure in Primary Proteinuric Glomerulopathies.

INTRODUCTION: Fibroblast growth factor 23 (FGF23) has direct effects on the vasculature and myocardium, and high levels of FGF23 are a risk factor for cardiovascular disease (CVD); however, the impact of FGF23 on CVD in primary proteinuric glomerulopathies has not been addressed. METHODS: The associations of baseline plasma intact FGF23 levels with resting blood pressure (BP) and lipids over time among adults and children with proteinuric glomerulopathies enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were analyzed using generalized estimating equation regression analyses. Models were adjusted for age, sex, glomerular diagnosis, follow-up time, estimated glomerular filtration rate, urine protein/creatinine ratio, obesity, and serum phosphorous levels. RESULTS: Two hundred and four adults with median FGF23 77.5 (IQR 51.3-119.3) pg/mL and 93 children with median FGF23 62.3 (IQR 44.6-83.6) pg/mL were followed for a median of 42 (IQR 20.5-54) months. In adjusted models, each 1 µg/mL increase in FGF23 was associated with a 0.3 increase in systolic BP index at follow-up (p < 0.001). Greater baseline FGF23 was associated with greater odds of hypertensive BP (OR = 1.0003; 95% CI 1.001-1.006, p = 0.03) over time. Compared to tertile 1, tertile 2 (OR = 2.1; 95% CI 1.12-3.99, p = 0.02), and tertile 3 (OR = 3; 95% CI 1.08-8.08, p = 0.04), FGF23 levels were associated with greater odds of hypertensive BP over time. Tertile 2 was associated with greater triglycerides compared to tertile 1 (OR = 48.1; 95% CI 4.4-91.9, p = 0.03). CONCLUSION: Overall, higher baseline FGF23 was significantly associated with hypertensive BP over time in individuals with proteinuric glomerulopathies. Further study of FGF23 as a therapeutic target for reducing CVD in proteinuric glomerular disease is warranted.

Gene Editing for the Treatment of Hypercholesterolemia.

PURPOSE OF REVIEW: Here, we summarize the key findings from preclinical studies that tested the concept that editing of hepatic genes can lower plasma low-density lipoprotein (LDL)-cholesterol levels to subsequently reduce atherosclerotic cardiovascular disease risk. RECENT FINDINGS: Selective delivery of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated gene editing tools targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to hepatocytes, i.e., through encapsulation into N-acetylgalactosamine-coupled lipid nanoparticles, is able to induce a stable ~ 90% decrease in plasma PCSK9 levels and a concomitant 60% reduction in LDL-cholesterol levels in mice and non-humane primates. Studies in mice have shown that this state-of-the-art technology can be extended to include additional targets related to dyslipidemia such as angiopoietin-like 3 and several apolipoproteins. The use of gene editors holds great promise to lower plasma LDL-cholesterol levels also in the human setting. However, gene editing safety has to be guaranteed before this approach can become a clinical success.

Subclinical Atherosclerosis to Guide Treatment in Dyslipidemia and Diabetes Mellitus.

PURPOSE OF REVIEW: Dyslipidemia and type 2 diabetes mellitus are two common conditions that are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). In this review, we aimed to provide an in-depth and contemporary review of non-invasive approaches to assess subclinical atherosclerotic burden, predict cardiovascular risk, and guide appropriate treatment strategies. We focused this paper on two main imaging modalities: coronary artery calcium (CAC) score and computed tomography coronary angiography. RECENT FINDINGS: Recent longitudinal studies have provided stronger evidence on the relationship between increased CAC, thoracic aorta calcification, and risk of cardiovascular events among those with primary hypercholesterolemia, highlighting the beneficial role of statin therapy. Interestingly, resilient profiles of individuals not exhibiting atherosclerosis despite dyslipidemia have been described. Non-conventional markers of dyslipidemia have also been associated with increased subclinical atherosclerosis presence and burden, highlighting the contribution of apolipoprotein B-100 (apoB)-rich lipoprotein particles, such as remnant cholesterol and lipoprotein(a), to the residual risk of individuals on-target for low-density lipoprotein cholesterol (LDL-C) goals. Regarding type 2 diabetes mellitus, variability in atherosclerotic burden has also been found, and CAC testing has shown significant predictive value in stratifying cardiovascular risk. Non-invasive assessment of subclinical atherosclerosis can help reveal the continuum of ASCVD risk in those with dyslipidemia and diabetes mellitus and can inform personalized strategies for cardiovascular disease prevention in the primary prevention setting.