Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms.

Genome-wide association studies in adults have identified variants in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6-0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective -TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down-regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

Comparison of the Lipidomic Signature of Fatty Liver in Children and Adults: A Cross-Sectional Study.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children characterised by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease. METHODS: We performed untargeted liquid chromatography-mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9500 adults with metabolic phenotyping. RESULTS: More severe paediatric NAFLD was associated with lower levels of long chain, polyunsaturated phosphatidylcholines (pC) and triglycerides (TG). Similar trends in pC and TG chain length and saturation were seen in adults with hepatic steatosis; however, many of the specific lipids associated with NAFLD differed between children and adults. Five lipids replicated in adults (including PC(36:4)) have been directly linked to death and cardiometabolic disease, as well as indirectly via genetic variants. CONCLUSION: These findings suggest that, whilst similar pathways of lipid metabolism are perturbed in paediatric NAFLD as in cardiometabolic disease in adults, the specific lipid signature in children is different.

Changes in Free-Living Glycemic Profiles after 12 Months of Lifestyle Intervention in Children with Overweight and with Obesity.

Previous studies demonstrated that hyperglycemic glucose concentrations are observed in children that are overweight or have obesity. The aim of this study was to evaluate the effect of a 12 month lifestyle intervention on free-living glycemic profiles in children that were overweight or had obesity, and the association of the alterations with changes in cardiovascular risk parameters. BMI z-score, free-living glycemic profiles, continuous overlapping net glycemic action (CONGA), and cardiovascular parameters were evaluated before and after a multidisciplinary lifestyle intervention, in 33 non-diabetic children that were overweight or had obesity. In children with a decrease in BMI z-score, the duration which glucose concentrations were above the high-normal threshold (6.7 mmol/L) and the glycemic variability decreased significantly. In these children, a decrease in median sensor glucose was associated with decreases in LDL-cholesterol, and systolic and diastolic blood pressure z-score. A decrease in BMI z-score was associated with a decrease in CONGA1, 2, and 4. In conclusion, the glycemic profiles in free-living conditions in children that were overweight improved in children with a decrease in BMI z-score after lifestyle intervention. In those children, changes in median sensor glucose concentrations were associated with changes in LDL-cholesterol and blood pressure z-scores. These results suggest that glucose homeostasis can improve after one year of lifestyle intervention and that these improvements are associated with improvements in cardiovascular health parameters.

Comorbidities in Primary vs Secondary School Children With Obesity and Responsiveness to Lifestyle Intervention.

CONTEXT: Childhood obesity increases the risk of diseases as diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. OBJECTIVE: To evaluate the prevalence of comorbidities in school-age children with obesity and to compare its prevalence and the effect of a lifestyle intervention between children in primary and secondary school and between boys and girls. DESIGN: Cross-sectional analysis and lifestyle intervention. SETTING: Centre for Overweight Adolescent and Children's Healthcare. PATIENTS: Comorbidities were evaluated in 149 primary and 150 secondary school children with (morbid) obesity (162 girls). The effect of lifestyle intervention was studied in 82 primary and 75 secondary school children. INTERVENTION: One-year interdisciplinary lifestyle intervention. RESULTS: Insulin resistance (37%), impaired glucose tolerance (IGT) (3%), dyslipidemia (48%), hypertension (7%), and elevated liver transaminase levels (54%) were already common in primary school children. Glomerular hyperfiltration and insulin resistance were more prevalent in secondary school children. IGT was more prevalent in girls. The change in body mass index z score after intervention was greater in primary school children (primary vs secondary: -0.25 ± 0.32 vs -0.11 ± 0.47), even as the change in low-density lipoprotein cholesterol concentrations [primary vs secondary: -0.30 (interquartile range, -0.70 to 0.10) vs -0.10 (interquartile range, -0.40 to 0.30)] and systolic blood pressure z score (primary vs secondary: -0.32 ± 1.27 vs 0.24 ± 1.3). The change in body mass index z score, but not in comorbidities, was greater in boys (boys vs girls: -0.33 ± 0.45 vs -0.05 ± 0.31). CONCLUSIONS: The presence of comorbidities is already evident in primary school children with obesity. The effect of a lifestyle intervention on these comorbidities is greater in primary compared with secondary school children, stressing the need for early interventions.

Characteristics of the retinal microvasculature in association with cardiovascular risk markers in children with overweight, obesity and morbid obesity.

To aim of this study was to evaluate characteristics of the retinal microvasculature, but particularly potential associations with classic and novel (endothelial function and low-grade inflammation)markers for cardiovascular risk, in a cohort of children with overweight and (morbid) obesity. Central retinal arteriolar equivalent(CRAE) and central retinal venular equivalent(CRVE) were assessed. CRAE was significantly lower and AVR significantly higher in children with morbid obesity than in children with overweight and normal weight(p < 0.01). CRVE did not differ significantly between the four weight categories. A multiple linear regression model with CRAE as dependent variable showed that only DBP z-score(ß = -2.848,p = 0.029) and plasma glucose concentrations(ß = 6.029,p = 0.019) contributed significantly to the variation in CRAE. Remarkably, despite a correlation between CRAE and circulating concentrations of the adhesion molecules VCAM-1 or ICAM-1, markers for inflammation and endothelial function did not contribute to the variation in CRAE. This is the first study showing in population of children with overweight and obesity that the retinal arteriolar microvasculature, but not venular diameter is aberrant, with increasing BMI z-score. CRAE was significantly associated with several cardiovascular risk markers, and multiple linear regression showed that a higher diastolic blood pressure z-score and lower fasting plasma glucose concentrations significantly contributed to the variance in CRAE.

Glycaemic Profiles of Children With Overweight and Obesity in Free-living Conditions in Association With Cardiometabolic Risk.

Insulin resistance is common among children with overweight and obesity. However, knowledge about glucose fluctuations in these children is scarce. This study aims to evaluate glycaemic profiles in children with overweight and obesity in free-living conditions, and to examine the association between glycaemic profiles with insulin resistance and cardiovascular risk parameters. One hundred eleven children with overweight and obesity were included. 48-hour sensor glucose concentrations in free-living conditions, fasting plasma and post-glucose load concentrations, serum lipid and lipoprotein concentrations, homeostatic model assessment of insulin resistance (HOMA-IR), and blood pressure were evaluated. Hyperglycaemic glucose excursions (≥7.8 mmol/L) were observed in 25% (n = 28) of the children. The median sensor glucose concentration was 5.0 (2.7-7.3) mmol/L, and correlated with fasting plasma glucose concentrations (rs = 0.190, p = 0.046), serum insulin concentrations (rs = 0.218, p = 0.021), and HOMA-IR (rs = 0.230, p = 0.015). The hyperglycaemic area under the curve (AUC) correlated with waist circumference z-score (rs = 0.455, p = 0.025), triacylglycerol concentrations (rs = 0.425, p = 0.024), and HOMA-IR (rs = 0.616, p < 0.001). In conclusion, hyperglycaemic glucose excursions are frequently observed in children with overweight and obesity in free-living conditions. Children with insulin resistance had higher median sensor glucose concentrations and a larger hyperglycaemic sensor glucose AUC, which are both associated with specific parameters predicting cardiovascular disease risk.