The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector for human VDR and performed transcriptomic and metabolomic analyses of cultured human hepatocytes upon VDR activation by vitamin D (VitD). Twenty percent of the VDR responsive genes were related to lipid metabolism, including MOGAT1, LPGAT1, AGPAT2, and DGAT1 (glycerolipid metabolism); CDS1, PCTP, and MAT1A (phospholipid metabolism); and FATP2, SLC6A12, and AQP3 (uptake of fatty acids, betaine, and glycerol, respectively). They were rapidly induced (4-6 h) upon VDR activation by 10 nM VitD or 100 µM lithocholic acid (LCA). Most of these genes were also upregulated by VDR/VitD in mouse livers in vivo. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics demonstrated intracellular accumulation of triglycerides, with concomitant decreases in diglycerides and phosphatidates, at 8 and 24 h upon VDR activation. Significant alterations in phosphatidylcholines, increases in lyso-phosphatidylcholines and decreases in phosphatidylethanolamines and phosphatidylethanolamine plasmalogens were also observed. In conclusion, active VitD/VDR signaling in hepatocytes triggers an unanticipated coordinated gene response leading to triglyceride synthesis and to important perturbations in glycerolipids and phospholipids

PTEN Deletion in Adult Mice Induces Hypoinsulinemia With Concomitant Low Glucose Levels

The PI3K/AKT pathway, negatively regulated by PTEN, plays a paramount role in glucose metabolism regulation due to its activation by the insulin receptor signaling pathway. We generated a PTEN-KO mouse to evaluate the systemic effect of the overactivation of the PI3K/AKT pathway in insulin signaling and glucose homeostasis. Our results demonstrate that PTEN-KO mice show very low glucose levels in the fasted state, which poorly respond to glucose and pyruvate administration. Insulinemia decreased without alterations in pancreatic islets. Among the possible reasons, we uncover the deregulation of the expression of proximal tubule glucose transporter and consequent glycosuria. Moreover, we evidence an altered activation of hepatic gluconeogenesis-related genes. In addition, the expression of several genes related to β-oxidation showed a delayed or even absent response to fasting, suggesting that the lack of PTEN not only impairs glucose metabolism but also slows down the use of lipids as a metabolic fuel. We conclude that the inducible full PTEN-KO mice could be a good model to study the metabolic interactions between glycidic and lipidic metabolism in hypoinsulinemic hypoglycemia and that PTEN could be an important mediator in the disease and/or a potential drug target

Do individuals with autoimmune disease have increased risk of subclinical carotid atherosclerosis and stiffness?

To explore the role of chronic inflammation inherent to autoimmune diseases in the development of subclinical atherosclerosis and arterial stiffness, this study recruited two population-based samples of individuals with and without autoimmune disease (ratio 1:5) matched by age, sex, and education level and with a longstanding (≥6 years) diagnosis of autoimmune disease. Common carotid intima media thickness (IMT) and arterial distensibility and compliance were assessed with carotid ultrasound. Multivariable linear and logistic regression models were adjusted for 10-year cardiovascular risk. In total, 546 individuals with and without autoimmune diseases (91 and 455, respectively) were included. Mean age was 66 years (standard deviation 12), and 240 (43.9%) were women. Arterial stiffness did not differ according to presence of autoimmune diseases. In men, the diagnosis of autoimmune diseases significantly increased common carotid IMT [beta-coefficient (95% confidence interval): 0.058 (0.009; 0.108); p-value=0.022] and the percentage having IMT ≥ percentile 75 [1.012 (0.145; 1.880); p-value=0.022]. Women without autoimmune disease were more likely to have IMT ≥ percentile 75 [-2.181 (-4.214; -0.149); p-value=0.035] but analysis of IMT as a continuous variable did not yield significant results. In conclusion, subclinical carotid atherosclerosis, but not arterial stiffness, was higher in men with autoimmune diseases. Women did not show significant differences in any of these carotid features. Sex was an effect modifier in the association between common carotid IMT values and the diagnosis of autoimmune diseases

Subclinical atherosclerosis burden predicts cardiovascular events in individuals with diabetes and chronic kidney disease

Background: Individuals with diabetes have remarkably high rates of cardiovascular morbidity and mortality. However, the incremental cardiovascular risk in diabetes is heterogeneous and has often been related to renal involvement. The purpose of this study was to analyse the prognostic value of subclinical atherosclerosis in determining the incidence of first cardiovascular events (CVEs) in individuals with diabetes and chronic kidney disease (CKD) compared to CKD individuals without diabetes. Methods: We included data from individuals with CKD with and without diabetes, free from pre-existing cardiovascular disease, from the NEFRONA cohort. Participants underwent baseline carotid and femoral ultrasound and were followed up for 4 years. All CVEs during follow-up were registered. Bivariate analysis and Fine-Gray competing risk models were used to perform the statistical analysis. Results: During the mean follow-up time of 48 months, a total of 203 CVE was registered. 107 CVE occurred among participants without diabetes (19.58 per 1000 person-years) and 96 CVE occurred among participants with diabetes (44.44 per 1000 person-years). Following the competing risk analysis, the variables predicting CVEs in CKD individuals without diabetes were the number of territories with plaque at baseline (HR 1.862, 95% CI [1.432;2.240]), age (HR 1.026, 95% CI [1.003;1.049]) and serum concentrations of 25-OH vitamin D (HR 0.963, 95% CI [0.933;0.094]). The only variable predicting CVEs among CKD participants with diabetes was the number of territories with plaque at baseline (HR 1.782, 95% CI [1.393, 2.278]). For both models, concordance (C) index yielded was over 0.7. Conclusions: The burden of subclinical atherosclerosis is the strongest predictor of future CVEs in diabetic individuals with CKD. Early detection of subclinical atherosclerotic burden by multiterritorial vascular ultrasound could improve CVE prediction in this population.Peer reviewe

The Increase in FGF23 Induced by Calcium Is Partially Dependent on Vitamin D Signaling

Background: Increased FGF23 levels are an early pathological feature in chronic kidney disease (CKD), causing increased cardiovascular risk. The regulation of FGF23 expression is complex and not completely understood. Thus, Ca2+ has been shown to induce an increase in FGF23 expression, but whether that increase is mediated by simultaneous changes in parathyroid hormone (PTH) and/or vitamin D is not fully known. Methods: Osteoblast-like cells (OLCs) from vitamin D receptor (VDR)+/+ and VDR−/− mice were incubated with Ca2+ for 18 h. Experimental hypercalcemia was induced by calcium gluconate injection in thyro-parathyroidectomized (T-PTX) VDR +/+ and VDR−/− mice with constant PTH infusion. Results: Inorganic Ca2+ induced an increase in FGF23 gene and protein expression in osteoblast-like cells (OLCs), but the increase was blunted in cells lacking VDR. In T-PTX VDR +/+ and VDR−/− mice with constant PTH levels, hypercalcemia induced an increase in FGF23 levels, but to a lower extent in animals lacking VDR. Similar results were observed in FGF23 expression in bone. Renal and bone 1α-hydroxylase expression was also modulated. Conclusions: Our study demonstrates that Ca2+ can increase FGF23 levels independently of vitamin D and PTH, but part of the physiological increase in FGF23 induced by Ca2+ is mediated by vitamin D signaling

Prevalence and progression of subclinical atherosclerosis in patients with chronic kidney disease and diabetes

Background and aims: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD) and diabetes. Traditional cardiovascular risk factors fail to fully account for the increase in cardiovascular risk in these patients. This study aims to analyse the prevalence and progression of subclinical atherosclerosis in CKD patients with and without diabetes. Methods: We included data from CKD patients with and without diabetes free from previous cardiovascular events from the NEFRONA cohort. Patients underwent baseline and 24-month follow-up carotid and femoral ultrasound examinations. Multivariable models were used to assess the contribution of diabetes to the presence and plaque progression. Results: A total of 419 patients with diabetes and 1129 without diabetes were included. Diabetic patients were older, had higher BMIs, more hypertension and dyslipidaemia. At baseline, the proportion of patients with plaque was higher among diabetic patients (81.4% vs. 64.1%, p <0.001). Diabetic patients more frequently had more than two vascular territories with plaque (64.4% vs. 48.4%, p <0.001). Multivariable analysis indicated that plaque at baseline was significantly associated with age, gender, smoking and renal replacement therapy (RRT) in the non-diabetic patients, but only with age and male gender in diabetic patients. Plaque progression was significantly associated with age, number of territories with basal plaque, smoking and RRT in both groups. Conclusions: Subclinical atherosclerosis is more prevalent, carries a higher plaque burden and is more rapidly progressive in renal patients with diabetes. In these patients, diabetes outweighs other described risk factors associated with the presence of subclinical atherosclerosis. (c) 2018 Elsevier B.V. All rights reserved.Peer reviewe