Enhanced Hepatic apoA-I Secretion and Peripheral Efflux of Cholesterol and Phospholipid in CD36 Null Mice

CD36 facilitates oxidized low density lipoprotein uptake and is implicated in development of atherosclerotic lesions. CD36 also binds unmodified high and very low density lipoproteins (HDL, VLDL) but its role in the metabolism of these particles is unclear. Several polymorphisms in the CD36 gene were recently shown to associate with serum HDL cholesterol. To gain insight into potential mechanisms for these associations we examined HDL metabolism in CD36 null (CD36−/−) mice. Feeding CD36−/− mice a high cholesterol diet significantly increased serum HDL, cholesterol and phospholipids, as compared to wild type mice. HDL apolipoproteins apoA-I and apoA-IV were increased and shifted to higher density HDL fractions suggesting altered particle maturation. Clearance of dual-labeled HDL was unchanged in CD36−/− mice and cholesterol uptake from HDL or LDL by isolated CD36−/− hepatocytes was unaltered. However, CD36−/− hepatocytes had higher cholesterol and phospholipid efflux rates. In addition, expression and secretion of apoA-I and apoA-IV were increased reflecting enhanced PXR. Similar to hepatocytes, cholesterol and phospholipid efflux were enhanced in CD36−/− macrophages without changes in protein levels of ABCA1, ABCG1 or SR-B1. However, biotinylation assays showed increased surface ABCA1 localization in CD36−/− cells. In conclusion, CD36 influences reverse cholesterol transport and hepatic ApoA-I production. Both pathways are enhanced in CD36 deficiency, increasing HDL concentrations, which suggests the potential benefit of CD36 inhibition

An Afferent Vagal Nerve Pathway Links Hepatic PPARα Activation to Glucocorticoid-Induced Insulin Resistance and Hypertension

SummaryGlucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPARα (Ppara) is required for glucocorticoid-induced insulin resistance. Here we demonstrate that afferent fibers of the vagus nerve interface with hepatic Ppara expression to disrupt blood pressure and glucose homeostasis in response to glucocorticoids. Selective hepatic vagotomy decreased hyperglycemia, hyperinsulinemia, hepatic insulin resistance, Ppara expression, and phosphoenolpyruvate carboxykinase (PEPCK) enzyme activity in dexamethasone-treated Ppara+/+ mice. Selective vagotomy also decreased blood pressure, adrenergic tone, renin activity, and urinary sodium retention in these mice. Hepatic reconstitution of Ppara in nondiabetic, normotensive dexamethasone-treated PPARα null mice increased glucose, insulin, hepatic PEPCK enzyme activity, blood pressure, and renin activity in sham-operated animals but not hepatic-vagotomized animals. Disruption of vagal afferent fibers by chemical or surgical means prevented glucocorticoid-induced metabolic derangements. We conclude that a dynamic interaction between hepatic Ppara expression and a vagal afferent pathway is essential for glucocorticoid induction of diabetes and hypertension

Hypotension due to Kir6.1 gain‐of‐function in vascular smooth muscle

BACKGROUND: K(ATP) channels, assembled from pore‐forming (Kir6.1 or Kir6.2) and regulatory (SUR1 or SUR2) subunits, link metabolism to excitability. Loss of Kir6.2 results in hypoglycemia and hyperinsulinemia, whereas loss of Kir6.1 causes Prinzmetal angina–like symptoms in mice. Conversely, overactivity of Kir6.2 induces neonatal diabetes in mice and humans, but consequences of Kir6.1 overactivity are unknown. METHODS AND RESULTS: We generated transgenic mice expressing wild‐type (WT), ATP‐insensitive Kir6.1 [Gly343Asp] (GD), and ATP‐insensitive Kir6.1 [Gly343Asp,Gln53Arg] (GD‐QR) subunits, under Cre‐recombinase control. Expression was induced in smooth muscle cells by crossing with smooth muscle myosin heavy chain promoter–driven tamoxifen‐inducible Cre‐recombinase (SMMHC‐Cre‐ER) mice. Three weeks after tamoxifen induction, we assessed blood pressure in anesthetized and conscious animals, as well as contractility of mesenteric artery smooth muscle and K(ATP) currents in isolated mesenteric artery myocytes. Both systolic and diastolic blood pressures were significantly reduced in GD and GD‐QR mice but normal in mice expressing the WT transgene and elevated in Kir6.1 knockout mice as well as in mice expressing dominant‐negative Kir6.1 [AAA] in smooth muscle. Contractile response of isolated GD‐QR mesenteric arteries was blunted relative to WT controls, but nitroprusside relaxation was unaffected. Basal K(ATP) conductance and pinacidil‐activated conductance were elevated in GD but not in WT myocytes. CONCLUSIONS: K(ATP) overactivity in vascular muscle can lead directly to reduced vascular contractility and lower blood pressure. We predict that gain of vascular K(ATP) function in humans would lead to a chronic vasodilatory phenotype, as indeed has recently been demonstrated in Cantu syndrome

The St. Louis African American health-heart study: methodology for the study of cardiovascular disease and depression in young-old African Americans

BACKGROUND: Coronary artery disease (CAD) is a major cause of death and disability worldwide. Depression has complex bidirectional adverse associations with CAD, although the mechanisms mediating these relationships remain unclear. Compared to European Americans, African Americans (AAs) have higher rates of morbidity and mortality from CAD. Although depression is common in AAs, its role in the development and features of CAD in this group has not been well examined. This project hypothesizes that the relationships between depression and CAD can be explained by common physiological pathways and gene-environment interactions. Thus, the primary aims of this ongoing project are to: a) determine the prevalence of CAD and depression phenotypes in a population-based sample of community-dwelling older AAs; b) examine the relationships between CAD and depression phenotypes in this population; and c) evaluate genetic variants from serotoninP and inflammatory pathways to discover potential gene-depression interactions that contribute significantly to the presence of CAD in AAs. METHODS/DESIGN: The St. Louis African American Health (AAH) cohort is a population-based panel study of community-dwelling AAs born in 1936–1950 (inclusive) who have been followed from 2000/2001 through 2010. The AAH-Heart study group is a subset of AAH participants recruited in 2009–11 to examine the inter-relationships between depression and CAD in this population. State-of-the-art CAD phenotyping is based on cardiovascular characterizations (coronary artery calcium, carotid intima-media thickness, cardiac structure and function, and autonomic function). Depression phenotyping is based on standardized questionnaires and detailed interviews. Single nucleotide polymorphisms of selected genes in inflammatory and serotonin-signaling pathways are being examined to provide information for investigating potential gene-depression interactions as modifiers of CAD traits. Information from the parent AAH study is being used to provide population-based prevalence estimates. Inflammatory and other biomarkers provide information about potential pathways. DISCUSSION: This population-based investigation will provide valuable information on the prevalence of both depression and CAD phenotypes in this population. The study will examine interactions between depression and genetic variants as modulators of CAD, with the intent of detecting mechanistic pathways linking these diseases to identify potential therapeutic targets. Analytic results will be reported as they become available

Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu

Highlights from the 24th workshop on vitamin D in Austin, September 2022

The 24th Workshop on Vitamin D was held September 7-9, 2022 in Austin, Texas and covered a wide diversity of research in the vitamin D field from across the globe. Here, we summarize the meeting, individual sessions, awards and presentations given

Bernal-Mizrachi Laboratory

Absence of Vitamin D receptor accelerates obesity-induced insulin resistance in mice.https://digitalcommons.wustl.edu/faculty_poster_session/1020/thumbnail.jp

Improving HbA1c with glucose self-monitoring in diabetic patients with EpxDiabetes, a phone call and text message-based telemedicine platform: A randomized controlled trial

Background: We conducted a randomized controlled trial of EpxDiabetes, a novel digital health intervention as an adjunct therapy to reduce HbA(1c) and fasting blood glucose (FBG) among patients with type 2 diabetes mellitus (T2DM). In addition, we examined the effect of social determinants of health on our system. Methods: Sixty-five (n = 65) patients were randomized at a primary care clinic. Self-reported FBG data were collected by EpxDiabetes automated phone calls or text messages. Only intervention group responses were shared with providers, facilitating follow-up and bidirectional communication. ΔHbA(1c) and ΔFBG were analyzed after 6 months. Results: There was an absolute HbA(1c) reduction of 0.69% in the intervention group (95% confidence interval [CI], −1.41 to 0.02) and an absolute reduction of 0.03% in the control group (95% CI, −0.88 to 0.82). For those with baseline HbA(1c) >8%, HbA(1c) decreased significantly by 1.17% in the intervention group (95% CI, −1.90 to −0.44), and decreased by 0.02% in the control group (95% CI, −0.99 to 0.94). FBG decreased in the intervention group by 21.6 mg/dL (95% CI, −37.56 to −5.639), and increased 13.0 mg/dL in the control group (95% CI, −47.67 to 73.69). Engagement (proportion responding to ≥25% of texts or calls over 4 weeks) was 58% for the intervention group (95% CI, 0.373–0.627) and 48% for the control group (95% CI, 0.296–0.621). Smoking, number of comorbidities, and response rate were significant predictors of ΔHbA(1c). Conclusions: EpxDiabetes helps to reduce HbA(1c) in patients with uncontrolled T2DM and fosters patient–provider communication; it has definite merit as an adjunct therapy in diabetes management. Future work will focus on improving the acceptability of the system and implementation on a larger scale trial

Admission hyperglycemia and radiological findings of SARS-CoV2 in patients with and without diabetes

Diabetes emerged as major risk factor for severe acute respiratory syndrome (SARS) and adverse outcome in patients with the coronavirus disease 2019 (COVID-19). Nevertheless, the role of admission hyperglycemia in patients with COVID-19 has not been well-explored, yet. With this retrospective analysis, we report for the first time that hyperglycemia on day-1 is the best predictor of radiographic imaging of SARS-CoV2, regardless of the past medical history of diabetes. Admission hyperglycemia should not be overlooked, but adequately treated to improve the outcomes of COVID-19 patients with our without diabetes