From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD.

Lanifibranor Reduces Inflammation and Improves Dyslipidemia in Lysosomal Acid Lipase-Deficient Mice.

Background And Aims: Recent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy; however, liver histopathology improved in some but not all patients. We hypothesized that the pan-peroxisome proliferator-activated receptor agonist lanifibranor may have beneficial effects on liver inflammation in LAL knockout (Lal-/-) mice based on its promising results in alleviating liver inflammation in patients with metabolic dysfunction-associated steatohepatitis.

Methods: Female Lal-/- mice were daily gavaged with lanifibranor or vehicle for 21 days.

Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.

Objective: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions.

Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase.

Lysosomal acid lipase (LAL) is the sole lysosomal enzyme responsible for the degradation of cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency (LAL-D), a severe and fatal disease characterized by ectopic lysosomal lipid accumulation. Reduced LAL activity also contributes to the development and progression of non-alcoholic fatty liver disease (NAFLD).

Impact of (intestinal) LAL deficiency on lipid metabolism and macrophage infiltration.

Objective: To date, the only enzyme known to be responsible for the hydrolysis of cholesteryl esters and triacylglycerols in the lysosome at acidic pH is lysosomal acid lipase (LAL). Lipid malabsorption in the small intestine (SI), accompanied by macrophage infiltration, is one of the most common pathological features of LAL deficiency. However, the exact role of LAL in intestinal lipid metabolism is still unknown.

Recent insights into lysosomal acid lipase deficiency.

Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid storage disorders with complete or partial absence of LAL activity. This review discusses the consequences of defective LAL-mediated lipid hydrolysis on cellular lipid homeostasis, epidemiology, and clinical presentation.

Monoglyceride Lipase Deficiency Is Associated with Altered Thrombogenesis in Mice.

Monoglyceride lipase (MGL) hydrolyzes monoacylglycerols (MG) to glycerol and one fatty acid. Among the various MG species, MGL also degrades 2-arachidonoylglycerol, the most abundant endocannabinoid and potent activator of the cannabinoid receptors 1 and 2. We investigated the consequences of MGL deficiency on platelet function using systemic (Mgl) and platelet-specific Mgl-deficient (platMgl) mice.

Dysregulation of Placental Lipid Hydrolysis by High-Fat/High-Cholesterol Feeding and Gestational Diabetes Mellitus in Mice.

Advanced maternal age and obesity are the main risk factors to develop gestational diabetes mellitus (GDM). Obesity is a consequence of the increased storage of triacylglycerol (TG). Cytosolic and lysosomal lipid hydrolases break down TG and cholesteryl esters (CE) to release fatty acids (FA), free cholesterol, and glycerol.

Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases.

Objectives: Lysosomal acid lipase (LAL) is the key enzyme, which degrades neutral lipids at an acidic pH in lysosomes. The role of LAL in various cellular processes has mostly been studied in LAL-knockout mice, which share phenotypical characteristics with humans suffering from LAL deficiency. In vitro, the cell-specific functions of LAL have been commonly investigated by using the LAL inhibitors Lalistat-1 and Lalistat-2.

Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth.

Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations.

ATG7 is dispensable for LC3-PE conjugation in thioglycolate-elicited mouse peritoneal macrophages.

Thioglycolate-elicited macrophages exhibit abundant conjugation of LC3 with PE (LC3-II). Among other autophagy-related (ATG) proteins, it is proposed that, like in yeast, both ATG5 and ATG7 are essential for LC3 conjugation. Using -deficient () and macrophages, we provide evidence that loss of ATG5 but not of ATG7 resulted in LC3-II depletion.

Urolithiasis in childhood: surgery and lithotripsy.

From 1982 through 1993, 174 interventions in 160 infants and children with urolithiasis were performed at our department. There were 101 boys and 59 girls, mean age 8.9 years.

Our 10-year experience with embolized Wilms' tumor.

In the Department of Pediatric Surgery, Clinical Hospital Center Rebro in Zagreb, during the last 10 years a new method of invasive diagnostic and at the same time therapeutic procedure for the treatment of Wilms' tumor has been introduced. The treatment is preoperative Percutaneous Transcatheter Intraarterial Embolization (PTIE) of the renal artery. The aim of this procedure is to reduce vascularization, to decrease the mass of kidney affected by the tumor, to separate it from the surrounding tissue, to decrease intraoperative spillage of malignant cells into the blood stream and their metastasizing.

[Modern diagnosis and treatment of pheochromocytoma in children].

Pheochromocytoma is a rare tumor of chromaffin tissue of the adrenal gland that synthesizes, stores and releases cathecolamines. In 10% of the patients it arises outside the adrenal gland, and has been called paraganglioma. The following study describes our experience in the diagnostic process and treatment of pheochromocytoma in two children, a 8-year-old boy with the right ureteral paraganglioma, and a 8-year-old girl with pheo-chromocytoma of the leftsuprarenal gland.

Cloacal exstrophy: a case report.

A case of an extremely rare type of cloacal exstrophy in a male infant with a normally developed subvesical part of the urinary system and external genitalia but absent distal colon segment is presented. The patient also had omphalocele, upper urinary tract anomalies and sacrococcygeal teratoma.

Congenital pulmonary arteriovenous fistula: a rare cause of cyanosis in childhood.

Two children (both females) aged 15 months and 4 years are described as very rare cases of central cyanosis in childhood being caused by a congenital pulmonary arteriovenous fistula. The initial diagnosis was made based on cyanosis and chest radiographs, with normal physical, ECG, and radiological findings of the heart. They had no family history of the Rendu-Weber-Osler syndrome.

[The present status of treatment of splenic injuries in children].

Small but very dangerous risk of postsplenectomic sepses gave rise to the examination of surgical attitudes of medical treatment of damaged and ruptured spleen. Some new ideas of immunology revealed the importance of the spleen in the protection of the host and serious defect of immunologic system if the spleen is removed. According to those ideas, ruptured spleen is to be retained by all means.

Percutaneous transluminal renal angioplasty (PTRA) as a method of therapy for renovascular hypertension in children.

The results of PTRA in treatment of renovascular hypertension in four children aged 5, 7, 13 and 15 are presented. All patients suffered from severe hypertension. Tests showed all of them to have fibromuscular dysplasia stenosis of the main renal artery and significant lateralization of renin levels.

Congenital ureteric diverticula in children and adults: classification, radiological and clinical features.

To date, about 100 cases of a blind-ending branch of a bifid ureter have been reported. We present 13 clinically, radiologically and histologically evaluated cases of congenital ureteric diverticulum. We believe this anomaly is not as rare as hitherto believed and suggest the term congenital ureteric diverticulum for a blind-ending branch of a bifid ureter.

Primary vesicoureteric reflux treated by antireflux ureterocystostomy at the vertex of the bladder. A 12-year follow-up and analysis of operative failure.

A total of 618 children with primary vesicoureteric reflux (VUR) were examined preoperatively and 6, 9 and 24 months after an antireflux ureterocystostomy of the vertex of the bladder (AUVB); 206 children were operated on bilaterally, so that 824 AUVBs were performed. Most patients had grade 3 or 4 reflux and only 5% had grade 2 reflux. Successful results were noted in 792 ureteric units; in 10 cases of post-operative stenosis and 17 cases of recurrent VUR a second AUVB was performed.

[Retroperitoneal hematoma in children with hemophilia].

The cases of two boys with hemophilia and retroperitoneal haematoma are presented; the diagnosis was confirmed by means of ultrasound scanning. The clinical picture of retroperitoneal haematoma can not be distinguished from other acute abdominal conditions (retroperitoneal infiltrate, or abscess). These pathological processes require surgical treatment, whereas such one in the patients suffering from haemophilia with retroperitoneal haematoma is contraindicated.