Article
Cell Biology
Kaiyuan Wu, Allen Seylani, Jing Wu, Xufeng Wu, Christopher K. E. Bleck, Michael N. Sack
Summary: The functional interaction of BLOC1S1 with the kinesin binding complex and the actin cytoskeleton are essential for lysosomal tubulation, which plays a key role in lysosome recycling through autophagic lysosome reformation (ALR).
Article
Endocrinology & Metabolism
Valentina Bianco, Melanie Korbelius, Nemanja Vujic, Alena Akhmetshina, Melina Amor, Dagmar Kolb, Anita Pirchheim, Ivan Bradic, Katharina B. Kuentzel, Martin Buerger, Silvia Schauer, Huyen T. T. Phan, Dominik Bulfon, Gerald Hoefler, Robert Zimmermann, Dagmar Kratky
Summary: The only known enzyme responsible for the hydrolysis of cholesteryl esters and triacylglycerols in the lysosome at acidic pH is lysosomal acid lipase (LAL). Lipid malabsorption with macrophage infiltration is a common feature of LAL deficiency, but the role of LAL in intestinal lipid metabolism is still unclear.
MOLECULAR METABOLISM
(2023)
Article
Biochemistry & Molecular Biology
Feifei Li, Xiaojie Zhao, Hao Li, Yu Liu, Yu Zhang, Xiaopeng Huang, Jia Cao, Fen Du, Dongfang Wu, Hong Yu
Summary: The absence of LAL leads to disruptions in cholesterol metabolism, while LAL overexpression helps lower lipid levels, reduce inflammation and oxidative stress, and improve liver health.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2021)
Article
Biochemistry & Molecular Biology
Jun-ichi Morishige, Kazuaki Yoshioka, Hiroki Nakata, Kazuhiro Ishimaru, Naoto Nagata, Tamotsu Tanaka, Yoh Takuwa, Hitoshi Ando
Summary: This study revealed a significant role of SphK1 in lysosomal integrity, which is crucial for energy consumption in brown adipose tissue. It further elucidates the mechanism underlying the association between S1P and brown adipose tissue.
JOURNAL OF LIPID RESEARCH
(2023)
Article
Gastroenterology & Hepatology
Rutiane Ullmann Thoen, Larisse Longo, Santiago Cassales Neto, Mario Reis Alvares-da-Silva
Summary: The study found that decreased LAL activity is associated with increased necroinflammatory activity and severity of the NAFLD activity score, providing new insights into the pathogenesis and progression of MAFLD.
CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY
(2021)
Article
Genetics & Heredity
Ursa Sustar, Urh Groselj, Katarina Trebusak Podkrajsek, Matej Mlinaric, Jernej Kovac, Martin Thaler, Ana Drole Torkar, Ajda Skarlovnik, Tadej Battelino, Tinka Hovnik
Summary: LAL-D is a lysosomal storage disorder that is often underdiagnosed or misdiagnosed due to similar clinical and laboratory findings with other cholesterol or liver dysfunctions. In a comprehensive familial hypercholesterolemia (FH) screening in Slovenia, LAL-D was screened as a secondary condition, and three children were identified with LAL-D through genetic analysis. Early treatment resulted in improved cholesterol and transaminase levels as well as liver steatosis in these children.
FRONTIERS IN GENETICS
(2022)
Editorial Material
Endocrinology & Metabolism
Alexander W. Fischer, Michelle Y. Jaeckstein, Joerg Heeren
Summary: Endothelial cells play a crucial role in the transport and processing of circulating nutrients and maintenance of tissue homeostasis. Recent studies have shown that capillary endothelial cells in thermogenic adipose tissues take up and metabolize triglyceride-rich lipoprotein particles in response to cold exposure, and this process is dependent on specific proteins and enzymes. Loss of lysosomal acid lipase in endothelial cells leads to impaired endothelial proliferation and diminished thermogenic adaptation. The processing of lipoproteins by lysosomal acid lipase generates reactive oxygen species, which in turn activate proliferative responses mediated by hypoxia-induced factor. This study provides in vivo evidence for the importance of lysosomal acid lipase in endothelial cells of thermogenic adipose tissue.
Article
Genetics & Heredity
Jane E. Potter, Gemma Petts, Arunabha Ghosh, Fiona J. White, Jane L. Kinsella, Stephen Hughes, Jane Roberts, Adam Hodgkinson, Kathryn Brammeier, Heather Church, Christine Merrigan, Joanne Hughes, Pamela Evans, Helen Campbell, Denise Bonney, William G. Newman, Brian W. Bigger, Alexander Broomfield, Simon A. Jones, Robert F. Wynn
Summary: The study describes a multimodal treatment approach for Wolman disease patients combining ERT, DSR, and HCT. After receiving HCT, patients showed improved disease phenotype and laboratory parameters, particularly in gastrointestinal symptoms. 4 out of 5 patients are alive, demonstrating the significant benefits of HCT in improving the condition of Wolman disease patients.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Genetics & Heredity
Xinying Hong, Yicheng Chen, Marianne Barr, Michael H. Gelb
Summary: The new enzymatic activity assay using a specific substrate provides an improved method for the diagnosis and prognosis of LAL-D patients, especially for asymptomatic individuals identified through newborn screening.
MOLECULAR GENETICS AND METABOLISM REPORTS
(2022)
Review
Health Policy & Services
Eleni Ioanna Katsigianni, Panagiotis Petrou
Summary: The objective of this paper is to assess the economic profile of enzyme replacement therapy (ERT) to patients with certain diseases. The results show that the Incremental Cost-Effectiveness Ratio greatly exceeds willingness to pay thresholds and the cost of medication dominates the sensitivity analysis. ERT is a promising treatment modality for orphan diseases, but it is also associated with a substantial economic burden.
COST EFFECTIVENESS AND RESOURCE ALLOCATION
(2022)
Review
Pediatrics
Hirokazu Kanegane, Atsuko Noguchi, Yuki Yamada, Takahiro Yasumi
Summary: Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder characterized by hypercytokinemia caused by excessive activation of cytotoxic T cells and macrophages. It can be primary or secondary, with primary HLH associated with genetic conditions and secondary HLH linked to infections, tumors, and autoimmune diseases. Rare diseases such as inborn errors of immunity (IEI) and inborn errors of metabolism (IEM) can also cause HLH.
PEDIATRICS INTERNATIONAL
(2023)
Review
Gastroenterology & Hepatology
Aamir Bashir, Ajay Duseja, Arka De, Manu Mehta, Pramil Tiwari
Summary: Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by the accumulation of excessive fat in the liver. It can occur in both obese and non-obese individuals, and its development is a complex, multifactorial process. The imbalance between lipid uptake, synthesis, and metabolism in the liver is the underlying mechanism, but the exact progression mechanism is not fully understood.
Article
Biochemistry & Molecular Biology
Qishun Zhou, Jakob Kerbl-Knapp, Fangrong Zhang, Melanie Korbelius, Katharina Barbara Kuentzel, Nemanja Vujic, Alena Akhmetshina, Gerd Hoerl, Margret Paar, Ernst Steyrer, Dagmar Kratky, Tobias Madl
Summary: Energy metabolism is closely related to aging and longevity, and metabolomics studies have provided insights into the changes in metabolite composition during aging. However, little is known about the metabolic changes in tissues responsible for food intake and lipid storage.
Article
Biochemistry & Molecular Biology
Melanie Korbelius, Nemanja Vujic, Katharina B. Kuentzel, Sascha Obrowsky, Silvia Rainer, Guenter Haemmerle, Thomas Ruelicke, Dagmar Kratky
Summary: The high expression of ATGL in enterocytes plays a critical role in modulating PPAR alpha and LXR signaling, thereby affecting whole-body cholesterol homeostasis and lipid metabolism.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2022)
Article
Cell Biology
Madeleine Goeritzer, Stefanie Schlager, Katharina B. Kuentzel, Nemanja Vujic, Melanie Korbelius, Silvia Rainer, Dagmar Kolb, Marion Mussbacher, Manuel Salzmann, Waltraud C. Schrottmaier, Alice Assinger, Axel Schlagenhauf, Corina T. Madreiter-Sokolowski, Sandra Blass, Thomas O. Eichmann, Wolfgang F. Graier, Dagmar Kratky
Summary: Loss of ATGL in platelets is associated with an anti-thrombogenic phenotype without pathological bleeding and platelet activation.
Article
Cell Biology
Lisha Joshi, Ioanna Plastira, Eva Bernhart, Helga Reicher, Zhanat Koshenov, Wolfgang F. Graier, Nemanja Vujic, Dagmar Kratky, Richard Rivera, Jerold Chun, Wolfgang Sattler
Summary: Systemic inflammation induces increased synthesis of LPA(5), which activates microglia and promotes neuroinflammation.
Article
Endocrinology & Metabolism
Ivan Bradic, Katharina B. Kuentzel, Sophie Honeder, Gernot F. Grabner, Nemanja Vujic, Robert Zimmermann, Ruth Birner-Gruenberger, Dagmar Kratky
Summary: Our findings demonstrate that Lalistat-1 and Lalistat-2 not only inhibit the action of LAL, but also suppress the activity of cytosolic lipid hydrolases responsible for lysosomal function. This has critical implications for understanding the role of LAL in lysosomal function, signaling pathways, and autophagy.
MOLECULAR METABOLISM
(2022)
Article
Biochemistry & Molecular Biology
Katharina B. Kuentzel, Ivan Bradic, Zala N. Mihalic, Melanie Korbelius, Silvia Rainer, Anita Pirchheim, Julia Kargl, Dagmar Kratky
Summary: Advanced maternal age and obesity are the main risk factors for gestational diabetes mellitus (GDM). In this study, we investigated the dysregulation of intracellular lipases in pregnancies complicated by maternal high-fat/high-cholesterol (HF/HCD) feeding with and without GDM. The results suggest that dysregulation of placental lipid hydrolysis may contribute to fetal hepatic lipid accumulation and fetal overgrowth.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Qishun Zhou, Fangrong Zhang, Jakob Kerbl-Knapp, Melanie Korbelius, Katharina Barbara Kuentzel, Nemanja Vujic, Alena Akhmetshina, Gerd Hoerl, Margret Paar, Ernst Steyrer, Dagmar Kratky, Tobias Madl
Summary: This study investigates the impact of PEMT on aging-associated energy metabolism using metabolomics. The results show that the effect of PEMT knockout is tissue-specific and age-dependent. Additionally, the absence of PEMT increases the divergence of the metabolome during aging in the liver, adipose tissues, and intestines.
Article
Biochemistry & Molecular Biology
Madeleine Goeritzer, Katharina B. Kuentzel, Sarah Beck, Melanie Korbelius, Silvia Rainer, Ivan Bradic, Dagmar Kolb, Marion Mussbacher, Waltraud C. Schrottmaier, Alice Assinger, Axel Schlagenhauf, Rene Rost, Benjamin Gottschalk, Thomas O. Eichmann, Thomas Zuellig, Wolfgang F. Graier, Nemanja Vujic, Dagmar Kratky
Summary: Monoglyceride lipase (MGL) hydrolyzes monoacylglycerols (MG) and plays a role in platelet function. MGL deficiency leads to decreased platelet aggregation and impaired response to collagen activation, resulting in reduced thrombus formation and prolonged bleeding time. Genetic deletion of MGL is associated with altered thrombogenesis in mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Melanie Korbelius, Katharina B. Kuentzel, Ivan Bradic, Nemanja Vujic, Dagmar Kratky
Summary: Lysosomal acid lipase (LAL) is an essential enzyme for degrading neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene can cause rare lysosomal lipid storage disorders, leading to reduced or absent LAL activity. This review discusses the impact of defective LAL-mediated lipid hydrolysis on cellular lipid homeostasis, epidemiology, and clinical presentation. Early detection of LAL deficiency (LAL-D) is crucial for disease management and survival. Enzyme replacement therapy, sometimes in combination with hematopoietic stem cell transplantation (HSCT), is currently the only therapy available for LAL-D. New technologies such as mRNA and viral vector gene transfer are being explored as potential therapeutic strategies.
TRENDS IN MOLECULAR MEDICINE
(2023)
Review
Biochemistry & Molecular Biology
Alena Akhmetshina, Dagmar Kratky, Elizabeth Rendina-Ruedy
Summary: This article discusses the regulatory role of cholesterol and its derivatives in osteoblast function and bone formation, as well as its association with osteoporosis and bone metastasis. It also highlights the molecular mechanisms underlying the interaction between cholesterol and osteoblasts.
Article
Biochemistry & Molecular Biology
Ivan Bradic, Laura Liesinger, Katharina B. Kuentzel, Nemanja Vujic, Michael Trauner, Ruth Birner-Gruenberger, Dagmar Kratky
Summary: Lysosomal acid lipase (LAL) is responsible for degrading cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency and non-alcoholic fatty liver disease (NAFLD). Comprehensive proteomic profiling of mouse livers with systemic or hepatocyte-specific loss of LAL revealed drastic proteome alterations in Lal-/- mice, including dysregulation of metabolism, inflammation, liver fibrosis, and cancer-related proteins. In contrast, hepLal-/- mice showed minor changes in the liver proteome, suggesting that loss of LAL solely in hepatocytes does not phenocopy the metabolic alterations observed in mice lacking LAL globally.
JOURNAL OF LIPID RESEARCH
(2023)
Article
Medicine, Research & Experimental
Yu Sun, Hadrien Demagny, Adrien Faure, Francesca Pontanari, Antoine Jalil, Nadia Bresciani, Ece Yildiz, Melanie Korbelius, Alessia Perino, Kristina Schoonjans
Summary: The enzyme asparagine synthetase (ASNS) is responsible for the de novo synthesis of the nonessential amino acid asparagine. The expression of ASNS in pericentral hepatocytes, specialized liver cells in xenobiotic detoxification, is significantly increased in models of acute liver injury. Mice with hepatocyte-specific Asns deletion are more susceptible to pericentral liver damage, which can be reversed by intravenous administration of asparagine. The upregulation of ASNS in response to stress is mediated by the nuclear receptor, liver receptor homolog 1 (LRH-1; NR5A2) through an ATF4-independent, noncanonical pathway.
JOURNAL OF CLINICAL INVESTIGATION
(2023)