Faculty Bibliography

OBJECTIVE:Aldose reductase (AKR1B1 in humans; Akr1b3 in mice), a key enzyme of the polyol pathway, mediates lipid accumulation in the murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 in the pathogenesis of obesity and its complications. METHODS:The study employed mice treated with an inhibitor of aldose reductase or mice devoid of Akr1b3 were used to determine their response to a high-fat diet. The study used subcutaneous adipose tissue-derived adipocytes to investigate mechanisms by which AKR1B1/Akr1b3 promotes diet-induced obesity. RESULTS:Increased expression of aldose reductase and senescence in the adipose tissue of humans and mice with obesity were demonstrated. Genetic deletion of Akr1b3 or pharmacological blockade of AKRIB3 with zopolrestat reduced high-fat-diet-induced obesity, attenuated markers of adipose tissue senescence, and increased lipolysis. CONCLUSIONS:AKR1B1/Akr1b3 modulation of senescence in subcutaneous adipose tissue contributes to aberrant metabolic responses to high-fat feeding. These data unveil new opportunities to target these pathways to combat obesity.

Obesity and non-alcoholic fatty liver disease (NAFLD) are on the rise world-wide; despite fervent advocacy for healthier diets and enhanced physical activity, these disorders persist unabated and, long-term, are major causes of morbidity and mortality. Numerous fundamental biochemical and molecular pathways participate in these events at incipient, mid- and advanced stages during atherogenesis and impaired regression of established atherosclerosis. It is proposed that upon the consumption of high fat/high sugar diets, the production of receptor for advanced glycation end products (RAGE) ligands, advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), contribute to the development of foam cells, endothelial injury, vascular inflammation, and, ultimately, atherosclerosis and its consequences. RAGE/Diaphanous-1 (DIAPH1) increases macrophage foam cell formation; decreases cholesterol efflux and causes foam cells to produce and release damage associated molecular patterns (DAMPs) molecules, which are also ligands of RAGE. DAMPs stimulate upregulation of Interferon Regulatory Factor 7 (IRF7) in macrophages, which exacerbates vascular inflammation and further perturbs cholesterol metabolism. Obesity and NAFLD, characterized by the upregulation of AGEs, ALEs and DAMPs in the target tissues, contribute to insulin resistance, hyperglycemia and type two diabetes. Once in motion, a vicious cycle of RAGE ligand production and exacerbation of RAGE/DIAPH1 signaling ensues, which, if left unchecked, augments cardiometabolic disease and its consequences. This Review focuses on RAGE/DIAPH1 and its role in perturbation of metabolism and processes that converge to augur cardiovascular disease.

Background/UNASSIGNED:Accruing evidence indicates that accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) play a significant role in obesity and type 2 diabetes. The concentrations of circulating RAGE isoforms, such as soluble RAGE (sRAGE), cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE), collectively sRAGE isoforms, may be implicit in weight loss and energy compensation resulting from caloric restriction. Objectives/UNASSIGNED:We aimed to evaluate whether baseline concentrations of sRAGE isoforms predicted changes (∆) in body composition [fat mass (FM), fat-free mass (FFM)], resting energy expenditure (REE), and adaptive thermogenesis (AT) during weight loss. Methods/UNASSIGNED:Data were collected during a behavioral weight loss intervention in adults with obesity. At baseline and 3 mo, participants were assessed for body composition (bioelectrical impedance analysis) and REE (indirect calorimetry), and plasma was assayed for concentrations of sRAGE isoforms (sRAGE, esRAGE, cRAGE). AT was calculated using various mathematical models that included measured and predicted REE. A linear regression model that adjusted for age, sex, glycated hemoglobin (HbA1c), and randomization arm was used to test the associations between sRAGE isoforms and metabolic outcomes. Results/UNASSIGNED:) experienced modest and variable weight loss over 3 mo. Although baseline sRAGE isoforms did not predict changes in ∆FM or ∆FFM, all baseline sRAGE isoforms were positively associated with ∆REE at 3 mo. Baseline esRAGE was positively associated with AT in some, but not all, AT models. The association between sRAGE isoforms and energy expenditure was independent of HbA1c, suggesting that the relation was unrelated to glycemia. Conclusions/UNASSIGNED:This study demonstrates a novel link between RAGE and energy expenditure in human participants undergoing weight loss.This trial was registered at clinicaltrials.gov as NCT03336411.

Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand-receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for dysfunction in hyperglycemia observed in both type 1 and type 2 diabetes. Recent evidence indicates that RAGE ligands, acting as damage-associated molecular patterns molecules, or DAMPs, through RAGE may impact interferon signaling pathways, specifically through upregulation of IRF7 (interferon regulatory factor 7), thereby heralding and evoking pro-inflammatory effects on vulnerable tissues. Although successful targeting of RAGE in the clinical milieu has, to date, not been met with success, recent approaches to target RAGE intracellular signaling may hold promise to fill this critical gap. This review focuses on recent examples of highlights and updates to the pathobiology of RAGE and DIAPH1 in diabetic complications.

Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by proteinaceous aggregate accumulation and neuroinflammation culminating in rapidly progressive lower and upper motor neuron death. To interrogate cell-intrinsic and inter-cell type perturbations in ALS, single-nucleus RNA sequencing was performed on the lumbar spinal cord in the murine ALS model SOD1^G93A transgenic and littermate control mice at peri-symptomatic onset stage of disease, age 90 days. This work uncovered perturbed tripartite synapse functions, complement activation and metabolic stress in the affected spinal cord; processes evidenced by cell death and proteolytic stress-associated gene sets. Concomitantly, these pro-damage events in the spinal cord co-existed with dysregulated reparative mechanisms. This work provides a resource of cell-specific niches in the ALS spinal cord and asserts that interwoven dysfunctional neuronal-glial communications mediating neurodegeneration are underway prior to overt disease manifestation and are recapitulated, in part, in the human post-mortem ALS spinal cord.

Diabetes is a leading cause of cardiovascular morbidity and mortality. Despite numerous treatments for cardiovascular disease (CVD), for patients with diabetes, these therapies provide less benefit for protection from CVD. These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify especially as the diabetes epidemic continues to expand. In this context, high levels of blood glucose stimulate the flux via aldose reductase (AR) pathway leading to metabolic and signaling changes in cells of the cardiovascular system. In animal models flux via AR in hearts is increased by diabetes and ischemia and its inhibition protects diabetic and non-diabetic hearts from ischemia-reperfusion injury. In mouse models of diabetic atherosclerosis, human AR expression accelerates progression and impairs regression of atherosclerotic plaques. Genetic studies have revealed that single nucleotide polymorphisms (SNPs) of the ALD2 (human AR gene) is associated with diabetic complications, including cardiorenal complications. This Review presents current knowledge regarding the roles for AR in the causes and consequences of diabetic cardiovascular disease and the status of AR inhibitors in clinical trials. Studies from both human subjects and animal models are presented to highlight the breadth of evidence linking AR to the cardiovascular consequences of diabetes.

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BACKGROUND AND AIMS/OBJECTIVE:Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS:We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS:AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS:In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.