Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to ß-amyloid clearance.

Microglial cells consume adenosine triphosphate (ATP) during phagocytosis to clear neurotoxic ß-amyloid in Alzheimer's disease (AD). However, the contribution of energy metabolism to microglial function in AD remains unclear. Here, we demonstrate that hexokinase 2 (HK2) is elevated in microglia from an AD mouse model (5xFAD) and AD patients. Genetic deletion or pharmacological inhibition of HK2 significantly promotes microglial phagocytosis, lowers the amyloid plaque burden and attenuates cognitive impairment in male AD mice. Notably, the ATP level is dramatically increased in HK2-deficient or inactive microglia, which can be attributed to a marked upregulation in lipoprotein lipase (LPL) expression and subsequent increase in lipid metabolism. We further show that two downstream metabolites of HK2, glucose-6-phosphate and fructose-6-phosphate, can reverse HK2-deficiency-induced upregulation of LPL, thus supporting ATP production and microglial phagocytosis. Our findings uncover a crucial role for HK2 in phagocytosis through regulation of microglial energy metabolism, suggesting a potential therapeutic strategy for AD by targeting HK2.

Actualización en deficiencia de lipasa ácida lisosomal: diagnóstico, tratamiento y seguimiento de los pacientes / Update on lysosomal acid lipase deficiency: Diagnosis, treatment and patient management

La deficiencia de lipasa ácida lisosomal (DLAL) es una enfermedad ultrarrara causada por un error congénito del metabolismo lipídico, que se caracteriza por el depósito de ésteres de colesterol y triglicéridos en el organismo. En pacientes con nula función enzimática la enfermedad se inicia en el período perinatal y es inevitablemente mortal durante el primer año de vida. En el resto de los casos el fenotipo es heterogéneo, aunque la mayoría de los pacientes desarrollan hepatopatía crónica y pueden presentar enfermedad cardiovascular prematura. Clásicamente, el tratamiento de la DLAL ha consistido en el uso de medidas de soporte, que no evitan su progresión. En 2015, las agencias reguladoras aprobaron el uso de una LAL recombinante humana para el tratamiento de la DLAL. Dicho tratamiento de sustitución enzimática a largo plazo se ha asociado con mejorías significativas de los parámetros lipídicos y hepáticos, incrementándose la supervivencia en lactantes con enfermedad rápidamente progresiva. La gravedad de la enfermedad, junto con la reciente disponibilidad de un tratamiento específico, hace especialmente relevante la necesidad de identificar a estos pacientes en la práctica clínica, aunque la baja prevalencia de la DLAL y el solapamiento clínico con otras enfermedades más frecuentes dificulta su reconocimiento. Con base en la evidencia científica publicada y la experiencia clínica e investigacional de los autores, el presente documento incluye recomendaciones prácticas para la identificación y la monitorización de los pacientes con DLAL, incluyendo un algoritmo diagnóstico, junto con una actualización de su tratamiento (AU)

Lysosomal acid lipase deficiency (LALD) is an ultra-rare disease caused by a congenital disorder of the lipid metabolism, characterized by the deposition of cholesterol esters and triglycerides in the organism. In patients with no enzyme function, the disease develops during the perinatal period and is invariably associated with death during the first year of life. In all other cases, the phenotype is heterogeneous, although most patients develop chronic liver diseases and may also develop an early cardiovascular disease. Treatment for LALD has classically included the use of supportive measures that do not prevent the progression of the disease. In 2015, regulatory agencies approved the use of a human recombinant LAL for the treatment of LALD. This long-term enzyme replacement therapy has been associated with significant improvements in the hepatic and lipid profiles of patients with LALD, increasing survival rates in infants with a rapidly progressive disease. Both the severity of LALD and the availability of a specific treatment highlight the need to identify these patients in clinical settings, although its low prevalence and the existing clinical overlap with other more frequent pathologies limit its diagnosis. In this paper we set out practical recommendations to identify and monitor patients with LALD, including a diagnostic algorithm, along with an updated treatment (AU)

Heparin and insulin in the management of hypertriglyceridemia-associated pancreatitis: case series and literature review

SUMMARY Severe hypertriglyceridemia accounts for up to 7% of all cases of acute pancreatitis. Heparin and insulin activate lipoprotein lipase (LPL), thereby reducing plasma triglyceride levels. However, the safety and efficacy of heparin and insulin in the treatment of hypertriglyceridemia-associated acute pancreatitis have not been well established yet. We successfully used heparin and insulin as first-line therapy in four consecutive patients with acute pancreatitis secondary to hypertriglyceridemia. In a literature search, we revised almost all reports published to date of patients managed successfully with this combination. Heparin and insulin appear to be a safe, effective, and inexpensive first-line therapy for hypertriglyceridemia-associated acute pancreatitis.

Heparin and insulin in the management of hypertriglyceridemia-associated pancreatitis: case series and literature review.

Severe hypertriglyceridemia accounts for up to 7% of all cases of acute pancreatitis. Heparin and insulin activate lipoprotein lipase (LPL), thereby reducing plasma triglyceride levels. However, the safety and efficacy of heparin and insulin in the treatment of hypertriglyceridemia-associated acute pancreatitis have not been well established yet. We successfully used heparin and insulin as first-line therapy in four consecutive patients with acute pancreatitis secondary to hypertriglyceridemia. In a literature search, we revised almost all reports published to date of patients managed successfully with this combination. Heparin and insulin appear to be a safe, effective, and inexpensive first-line therapy for hypertriglyceridemia-associated acute pancreatitis.

Introduction to gene therapy: a clinical aftermath.

Despite three decades of huge progress in molecular genetics, in cloning of disease causative gene as well as technology breakthroughs in viral biotechnology, out of thousands of gene therapy clinical trials that have been initiated, only very few are now reaching regulatory approval. We shall review some of the major hurdles, and based on the current either positive or negative examples, we try to initiate drawing a learning curve from experience and possibly identify the major drivers for future successful achievement of human gene therapy trials.