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Cholesterol ester storage disorder

Sonia Ortiz-Miranda, Rui Ji, Agata Jurczyk, Ken-Edwin Aryee, Shunyan Mo, Terry Fletcher, Scott A Shaffer, Dale L Greiner, Rita Bortell, Ronald Gregg, Alan Cheng, Leah J Hennings, Ann R Rittenhouse
Knockout technology has proven useful for delineating functional roles of specific genes. Here we describe and provide an explanation for striking pathology that occurs in a subset of genetically engineered mice expressing a rat CaVβ2a transgene under control of the cardiac α-myosin heavy chain promoter. Lesions were limited to mice homozygous for transgene and independent of native Cacnb2 genomic copy number. Gross findings included an atrophied pancreas, decreased adipose tissue, thickened, orange intestines, and enlarged liver, spleen and abdominal lymph nodes...
September 22, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Nosratola D Vaziri
Nephrotic syndrome results in hyperlipidemia and profound alterations in lipid and lipoprotein metabolism. Serum cholesterol, triglycerides, apolipoprotein B (apoB)-containing lipoproteins (very low-density lipoprotein [VLDL], immediate-density lipoprotein [IDL], and low-density lipoprotein [LDL]), lipoprotein(a) (Lp[a]), and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are increased in nephrotic syndrome. This is accompanied by significant changes in the composition of various lipoproteins including their cholesterol-to-triglyceride, free cholesterol-to-cholesterol ester, and phospholipid-to-protein ratios...
July 2016: Kidney International
Walter L Miller
Steroidogenesis begins with cellular internalization of low-density lipoprotein particles and subsequent intracellular processing of cholesterol. Disorders in these steps include Adrenoleukodystrophy, Wolman Disease and its milder variant Cholesterol Ester Storage Disease, and Niemann-Pick Type C Disease, all of which may present with adrenal insufficiency. The means by which cholesterol is directed to steroidogenic mitochondria remains incompletely understood. Once cholesterol reaches the outer mitochondrial membrane, its delivery to the inner mitochondrial membrane is regulated by the steroidogenic acute regulatory protein (StAR)...
March 6, 2016: Journal of Steroid Biochemistry and Molecular Biology
Sofie M A Walenbergh, Tom Houben, Tim Hendrikx, Mike L J Jeurissen, Patrick J van Gorp, Nathalie Vaes, Steven W M Olde Damink, Fons Verheyen, Ger H Koek, Dieter Lütjohann, Alena Grebe, Eicke Latz, Ronit Shiri-Sverdlov
Recently, the importance of lysosomes in the context of the metabolic syndrome has received increased attention. Increased lysosomal cholesterol storage and cholesterol crystallization inside macrophages have been linked to several metabolic diseases, such as atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Two-hydroxypropyl-β-cyclodextrin (HP-B-CD) is able to redirect lysosomal cholesterol to the cytoplasm in Niemann-Pick type C1 disease, a lysosomal storage disorder. We hypothesize that HP-B-CD ameliorates liver cholesterol and intracellular cholesterol levels inside Kupffer cells (KCs)...
2015: International Journal of Molecular Sciences
Naomi Kuranobu, Jun Murakami, Ken Okamoto, Rei Nishimura, Kei Murayama, Ayumi Takamura, Toshiko Umeda, Yoshikatsu Eto, Susumu Kanzaki
Cholesterol ester storage disease (CESD) is an autosomal recessive disorder caused by deficient lysosomal acid lipase (LAL) activity, resulting in cholesteryl ester (CE) accumulation. CESD patients have liver disease associated with mixed dyslipidemia leading to liver failure. We here report the case of an 11-year-old male CESD patient with a novel mutation who had the chief complaint of massive hepatomegaly. The patient's liver reached to his pelvis, and his spleen was 2 cm below the costal margin. The patient had elevated serum liver enzymes and mixed dyslipidemia...
March 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Adam M Lopez, Jen-Chieh Chuang, Kenneth S Posey, Taichi Ohshiro, Hiroshi Tomoda, Lawrence L Rudel, Stephen D Turley
In most organs, the bulk of cholesterol is unesterified, although nearly all possess a varying capability of esterifying cholesterol through the action of either sterol O-acyltransferase (SOAT) 1 or, in the case of hepatocytes and enterocytes, SOAT2. Esterified cholesterol (EC) carried in plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease or cholesteryl ester storage disease (CESD)...
November 2015: Journal of Pharmacology and Experimental Therapeutics
Danijela Petković Ramadža, Mario Ćuk, Karin Zibar, Marina Barić, Vladimir Sarnavka, Karmen Bilić, Ksenija Fumić, Jurica Vuković, Silvija Pušeljić, Marijana Ćorić, Ranka Štern Padovan, Marko Kralik, Ivo Barić
Lysosomal acid lipase deficiency is an autosomal recessive disorder with two distinct clinical phenotypes. Wolman disease is rapidly progressive with onset in early infancy. Complete enzyme deficiency results in massive accumulation of cholesterol esters and triglycerides in intestines, liver, spleen and other monocyte-macrophage system cells causing malabsorption, hepatosplenomegaly, liver failure and death in early infancy. Cholesterol ester storage disease may be diagnosed in childhood or later in life. It is characterized by chronic course and variable progression...
March 2015: Lijec̆nic̆ki Vjesnik
Soraia Poloni, Henk J Blom, Ida V D Schwartz
An association between sulfur amino acids (methionine, cysteine, homocysteine and taurine) and lipid metabolism has been described in several experimental and population-based studies. Changes in the metabolism of these amino acids influence serum lipoprotein concentrations, although the underlying mechanisms are still poorly understood. However, recent evidence has suggested that the enzyme stearoyl-CoA desaturase-1 (SCD-1) may be the link between these two metabolic pathways. SCD-1 is a key enzyme for the synthesis of monounsaturated fatty acids...
2015: Biology
Ariel Brautbar, Emili Leary, Kristen Rasmussen, Don P Wilson, Robert D Steiner, Salim Virani
Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling...
April 2015: Current Atherosclerosis Reports
Adam M Lopez, Kenneth S Posey, Stephen D Turley
Sterol O-acyltransferase 2 (SOAT2), also known as ACAT2, is the major cholesterol esterifying enzyme in the liver and small intestine (SI). Esterified cholesterol (EC) carried in certain classes of plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease (WD) or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders...
November 7, 2014: Biochemical and Biophysical Research Communications
Anthony F Porto
Lysosomal acid lipase (LAL) is responsible for the hydrolysis of cholesterol esters and triglycerides. LAL is coded by the LIPA gene on chromosome 10q23.31. Its deficiency leads to two autosomal recessive disorders, Wolman disease (WD) and Cholesteryl Ester Storage Disease (CESD). WD has an estimated incidence of 1 in 500,000 live births and is the result of a complete loss of LAL and presents in infancy with vomiting, diarrhea, poor weight gain and hepatomegaly subsequently leading to death. CESD is the result of partial loss of LAL and its presentation is more variable...
September 2014: Pediatric Endocrinology Reviews: PER
Meghmala Sadhukhan, Amit Saha, Roshni Vara, Bim Bhaduri
Lysosomal acid lipase (LAL) deficiency is a rare autosomal recessive disorder which causes two distinct clinical phenotypes: Wolman's disease and cholesterol ester storage disease. LAL hydrolyses LDL-derived triglycerides and cholesterol esters to glycerol or cholesterol and free fatty acids. Its deficiency leads to accumulation of intracellular triglycerides and/or cholesterol esters. In early onset LAL deficiency, clinical manifestations start in the first few weeks of life with persistent vomiting, failure to thrive, hepatosplenomegaly, liver dysfunction and hepatic failure...
2014: BMJ Case Reports
Anna Tylki-Szymańska, Agnieszka Jurecka
Cholesteryl ester storage disease (CESD, OMIM #278000) and Wolman disease (OMIM #278000) are autosomal recessive lysosomal storage disorders caused by a deficient activity of lysosomal acid lipase (cholesteryl ester hydrolase, LAL). Human lysosomal acid lipase is essential for the metabolism of cholesteryl esters and triglycerides. In Wolman disease, LAL activity is usually absent, whereas CESD usually presents some residual LAL activity. In infants, poor weight gain, massive hepatosplenomegaly, calcified adrenal glands (present about 2/3 of the time), vomiting, diarrhea and failure to thrive are indicative of Wolman disease...
2014: Prilozi (Makedonska Akademija Na Naukite i Umetnostite. Oddelenie za Medicinski Nauki)
G Civallero, J De Mari, C Bittar, M Burin, R Giugliani
Lysosomal acid lipase (LAL) deficiency produces two well defined inborn disorders, Wolman disease (WD) and cholesteryl ester storage disease (CESD). WD is a severe, early-onset condition involving massive storage of triglycerides and cholesteryl esters in the liver, with death usually occurring before one year of life. CESD is a more attenuated, later-onset disease that leads to a progressive and variable liver dysfunction. Diagnosis of LAL deficiency is mainly based on the enzyme assay of LAL activity in fibroblasts...
April 10, 2014: Gene
F Freudenberg, P Bufler, R Ensenauer, P Lohse, S Koletzko
Cholesteryl ester storage disease (CESD) is a rare, autosomal recessively inherited disorder resulting from deficient activity of lysosomal acid lipase (LAL). LAL is the key enzyme hydrolyzing cholesteryl esters and triglycerides stored in lysosomes after LDL receptor-mediated endocytosis. Mutations within the LIPA gene locus on chromosome 10q23.2-q23.3 may result either in the always fatal Wolman disease, where no LAL activity is found, or in the more benign disorder CESD with a reduced enzymatic activity, leading to massive accumulation of cholesteryl esters and triglycerides in many body tissues...
October 2013: Zeitschrift Für Gastroenterologie
Nathan O Stitziel, Sigrid W Fouchier, Barbara Sjouke, Gina M Peloso, Alessa M Moscoso, Paul L Auer, Anuj Goel, Bruna Gigante, Timothy A Barnes, Olle Melander, Marju Orho-Melander, Stefano Duga, Suthesh Sivapalaratnam, Majid Nikpay, Nicola Martinelli, Domenico Girelli, Rebecca D Jackson, Charles Kooperberg, Leslie A Lange, Diego Ardissino, Ruth McPherson, Martin Farrall, Hugh Watkins, Muredach P Reilly, Daniel J Rader, Ulf de Faire, Heribert Schunkert, Jeanette Erdmann, Nilesh J Samani, Lawrence Charnas, David Altshuler, Stacey Gabriel, John J P Kastelein, Joep C Defesche, Aart J Nederveen, Sekar Kathiresan, G Kees Hovingh
OBJECTIVE: Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family...
December 2013: Arteriosclerosis, Thrombosis, and Vascular Biology
Peter E Thelwall, Fiona E Smith, Mark C Leavitt, David Canty, Wei Hu, Kieren G Hollingsworth, Christian Thoma, Michael I Trenell, Roy Taylor, Joseph V Rutkowski, Andrew M Blamire, Anthony G Quinn
BACKGROUND & AIMS: Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues. We used (1)H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency rat model. Secondly, we used MR spectroscopy to monitor the effects of an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model...
September 2013: Journal of Hepatology
Graeme K Ambler, Matthew Hoare, Rebecca Brais, Ashley Shaw, Andrew Butler, Paul Flynn, Patrick Deegan, William J H Griffiths
Cholesterol ester storage disease (CESD) is a rare autosomal recessive lipid storage disorder associated with mutations of the gene encoding lysosomal acid lipase, manifestations of which include chronic liver disease and early atherosclerosis. Although normally presenting in childhood, severity is variable and the condition can occasionally remain undetected until middle age. Typical presentation is with asymptomatic hepatosplenomegaly and hyperlipidaemia, though the condition is probably underdiagnosed. Treatment is supportive and may include attention to cardiovascular risk factors...
2013: JIMD Reports
Stuart A Scott, Benny Liu, Irina Nazarenko, Suparna Martis, Julia Kozlitina, Yao Yang, Charina Ramirez, Yumi Kasai, Tommy Hyatt, Inga Peter, Robert J Desnick
UNLABELLED: Cholesteryl ester storage disease (CESD) and Wolman disease are autosomal recessive later-onset and severe infantile disorders, respectively, which result from the deficient activity of lysosomal acid lipase (LAL). LAL is encoded by LIPA (10q23.31) and the most common mutation associated with CESD is an exon 8 splice junction mutation (c.894G>A; E8SJM), which expresses only ∼3%-5% of normally spliced LAL. However, the frequency of c.894G>A is unknown in most populations...
September 2013: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Donald F Farrell
Neonatal adrenoleukodystrophy constitutes a distinct genetic disorder of autosomal recessive inheritance, and is distinguishable from the cerebro-hepato-renal syndrome of Zellweger and X-linked juvenile adrenoleukodystrophy, although all three conditions store very long chain fatty acids. Abnormal clinical features in neonatal adrenoleukodystrophy are generally present at birth, and include muscle hypotonia, severe psychomotor retardation, and failure to thrive. These infants are generally blind and deaf, with seizures developing during their first few weeks...
November 2012: Pediatric Neurology
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