المؤلفون: Coates, Hudson W, Nguyen, Tina B, Du, Ximing, Olzomer, Ellen M, Farrell, Rhonda, Byrne, Frances L, Yang, Hongyuan, Brown, Andrew J

مصطلحات موضوعية: cancer, cholesterol, lipid droplets, protein degradation, squalene monooxygenase, Female, Humans, Cell Line, Tumor, Endometrial Neoplasms, Endoplasmic Reticulum, Gene Expression Regulation, Neoplastic, Up-Regulation

الوصف: Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we examined its lipid droplet-localized pool using complementary immunofluorescence and cell fractionation approaches and found that it exclusively comprises the truncated enzyme. This partitioning is facilitated by the loss of an endoplasmic reticulum-embedded region at the SM N terminus, whereas the catalytic domain containing membrane-associated C-terminal helices is spared. Moreover, we determined multiple amphipathic helices contribute to the lipid droplet localization of truncated SM. Taken together, our results expand on the striking differences between the two forms of SM and suggest upregulated truncation may contribute to SM-related oncogenesis.

وصف الملف: Print-Electronic; application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/369344Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/369344Test

المؤلفون: Chen, Sing-Young, Beretta, Martina, Olzomer, Ellen M., Alexopoulos, Stephanie J., Shah, Divya P., Byrne, Frances L., Salamoun, Joseph M., Garcia, Christopher J., Smith, Greg C., Larance, Mark, Philp, Andrew, Turner, Nigel, Santos, Webster L., Cantley, James, Hoehn, Kyle L.

المصدر: Chen , S-Y , Beretta , M , Olzomer , E M , Alexopoulos , S J , Shah , D P , Byrne , F L , Salamoun , J M , Garcia , C J , Smith , G C , Larance , M , Philp , A , Turner , N , Santos , W L , Cantley , J & Hoehn , K L 2024 , ' Head-to-head comparison of BAM15, semaglutide, rosiglitazone, NEN, and calorie restriction on metabolic physiology in female db/db mice ' , BBA - Molecular Basis of Disease , vol. 1870 ....

مصطلحات موضوعية: Mitochondrial uncoupling, Diabetes, Obesity, GLP-1, Calorie restriction, /dk/atira/pure/subjectarea/asjc/1300/1313, name=Molecular Medicine, /dk/atira/pure/subjectarea/asjc/1300/1312, name=Molecular Biology

الوصف: Metabolic disorders such as type 2 diabetes, fatty liver disease, hyperlipidemia, and obesity commonly co-occur but clinical treatment options do not effectively target all disorders. Calorie restriction, semaglutide, rosiglitazone, and mitochondrial uncouplers have all demonstrated efficacy against one or more obesity-related metabolic disorders, but it currently remains unclear which therapeutic strategy best targets the combination of hyperglycaemia, liver fat, hypertriglyceridemia, and adiposity. Herein we performed a head-to-head comparison of 5 treatment interventions in the female db/db mouse model of severe metabolic disease. Treatments included ∼60 % calorie restriction (CR), semaglutide, rosiglitazone, BAM15, and niclosamide ethanolamine (NEN). Results showed that BAM15 and CR improved body weight and liver steatosis to levels superior to semaglutide, NEN, and rosiglitazone, while BAM15, semaglutide, and rosiglitazone improved glucose tolerance better than CR and NEN. BAM15, CR, semaglutide, and rosiglitazone all had efficacy against hypertriglyceridaemia. These data provide a comprehensive head-to-head comparison of several key treatment strategies for metabolic disease and highlight the efficacy of mitochondrial uncoupling to correct multiple facets of the metabolic disease milieu in female db/db mice.

وصف الملف: application/pdf

العلاقة: https://discovery.dundee.ac.uk/en/publications/b653b5a5-e77e-47fb-ac5d-7995a51b5f3cTest

الإتاحة: https://doi.org/10.1016/j.bbadis.2023.166908Test
https://discovery.dundee.ac.uk/en/publications/b653b5a5-e77e-47fb-ac5d-7995a51b5f3cTest
https://discovery.dundee.ac.uk/ws/files/108817961/1-s2.0-S0925443923002740-main.pdfTest
http://www.scopus.com/inward/record.url?scp=85172989886&partnerID=8YFLogxKTest

المؤلفون: Chen, Sing-Young, Telfser, Aiden J., Olzomer, Ellen M., Vancuylenberg, Calum S., Zhou, Mingyan, Beretta, Martina, Li, Catherine, Alexopoulos, Stephanie J., Turner, Nigel, Byrne, Frances L., Santos, Webster L., Hoehn, Kyle L.

المساهمون: National Health and Medical Research Council, Division of Diabetes, Endocrinology, and Metabolic Diseases

المصدر: Clinical Science ; volume 138, issue 4, page 173-187 ; ISSN 0143-5221 1470-8736

مصطلحات موضوعية: General Medicine

الوصف: Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects.

الإتاحة: https://doi.org/10.1042/cs20231016Test
https://portlandpress.com/clinsci/article-pdf/138/4/173/954288/cs-2023-1016.pdfTest

المؤلفون: Coates, Hudson W., Nguyen, Tina B., Du, Ximing, Olzomer, Ellen M., Farrell, Rhonda, Byrne, Frances L., Yang, Hongyuan, Brown, Andrew J.

المساهمون: Australian Research Council

المصدر: Journal of Biological Chemistry ; page 107232 ; ISSN 0021-9258

الإتاحة: https://doi.org/10.1016/j.jbc.2024.107232Test
https://api.elsevier.com/content/article/PII:S0021925824017290?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0021925824017290?httpAccept=text/plainTest

المؤلفون: Hargett, Stefan, Lahiri, Sujoy, Kowalski, Greg M., Corley, Susan, Nelson, Marin E., Lackner, Carolin, Olzomer, Ellen M., Aleksovska, Isabella, Hearn, Brandon A., Shrestha, Riya, Janitz, Michael, Gorrell, Mark D., Bruce, Clinton R., Wilkins, Marc, Hoehn, Kyle L., Byrne, Frances L.

المساهمون: National Health and Medical Research Council, Cancer Institute NSW

المصدر: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ; volume 1870, issue 3, page 167029 ; ISSN 0925-4439

مصطلحات موضوعية: Molecular Biology, Molecular Medicine

الإتاحة: https://doi.org/10.1016/j.bbadis.2024.167029Test
https://api.elsevier.com/content/article/PII:S0925443924000140?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0925443924000140?httpAccept=text/plainTest

المؤلفون: Chen, Sing -Young, Beretta, Martina, Olzomer, Ellen M., Shah, Divya P., Wong, Derek Y. H., Alexopoulos, Stephanie J., Aleksovska, Isabella, Salamoun, Joseph M., Garcia, Christopher J., Cochran, Blake J., Rye, Kerry-Anne, Smith, Greg C., Byrne, Frances L., Morris, Margaret J., Santos, Webster L., Cantley, James, Hoehn, Kyle L.

مصطلحات موضوعية: Calorie restriction, Mitochondrial uncoupling, Obesity, Diabetes

الوصف: Objective: Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver. Methods: Male db/db mice were treated with w50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR. Results: Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis. Conclusions: BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects ...

وصف الملف: application/pdf

العلاقة: 101684; http://hdl.handle.net/10919/114173Test; https://doi.org/10.1016/j.molmet.2023.101684Test; 69

الإتاحة: https://doi.org/10.1016/j.molmet.2023.101684Test
http://hdl.handle.net/10919/114173Test

المؤلفون: Coates, Hudson W, Capell-Hattam, Isabelle M, Olzomer, Ellen M, Du, Ximing, Farrell, Rhonda, Yang, Hongyuan, Byrne, Frances L, Brown, Andrew J

مصطلحات موضوعية: Cholesterol, Hypoxia, Squalene monooxygenase, biochemistry, chemical biology, human, proteasome, protein degradation, Humans, Squalene, Oxygen

الوصف: Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. This preserves SM activity and downstream pathway flux during hypoxia. These results uncover a feedforward mechanism that allows SM to accommodate fluctuating substrate levels and may contribute to its widely reported oncogenic properties.

وصف الملف: application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/349398Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/349398Test

المؤلفون: Beretta, Martina, Dai, Yumin, Olzomer, Ellen M., Vancuylenburg, Calum S., Santiago-Rivera, José A., Philp, Ashleigh M., Hargett, Stefan R., Li, Keyong, Shah, Divya P., Chen, Sing-Young, Alexopoulos, Stephanie J., Li, Catherine, Harris, Thurl E., Lee, Brendan, Wathier, Michel, Cermak, Jennifer M., Tucker, Simon P., Turner, Nigel, Bayliss, Douglas A., Philp, Andrew

المصدر: Diabetes; Mar2024, Vol. 73 Issue 3, p374-384, 11p

مصطلحات موضوعية: GLUCOSE intolerance, FATTY liver, METABOLIC disorders, BODY composition, OBESITY, MITOCHONDRIA, DISEASE risk factors

مستخلص: Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities, including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation. Herein, we report the in vitro and in vivo characterization of compound SHD865, the first compound to be studied in vivo in a newly discovered class of imidazolopyrazine mitochondrial uncouplers. SHD865 is a derivative of the furazanopyrazine uncoupler BAM15. SHD865 is a milder mitochondrial uncoupler than BAM15 that results in a lower maximal respiration rate. In a mouse model of diet-induced adiposity, 6-week treatment with SHD865 completely restored normal body composition and glucose tolerance to levels like those of chow-fed controls, without altering food intake. SHD865 treatment also corrected liver steatosis and plasma hyperlipidemia to normal levels comparable with chow-fed controls. SHD865 has maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. Collectively, these data identify the potential of imidazolopyrazine mitochondrial uncouplers as drug candidates for the treatment of obesity-related disorders. Article Highlights: A growing body of evidence suggests that targeting negative energy balance with mitochondrial uncouplers has potential for the treatment of metabolic disease. We report the discovery and characterization of compound SHD865 as a new class imidazolopyrazine mitochondrial uncoupler. SHD865 is liver selective, safely reverses diet-induced adiposity, and improves glucose homeostasis in mice without altering food intake or decreasing lean mass. SHD865 and related compounds have translational potential for the treatment of obesity, diabetes, and related metabolic disorders. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Sing-Young Chen, Telfser, Aiden J., Olzomer, Ellen M., Vancuylenberg, Calum S., Mingyan Zhou, Beretta, Martina, Li, Catherine, Alexopoulos, Stephanie J., Turner, Nigel, Byrne, Frances L., Santos, Webster L., Hoehn, Kyle L.

المصدر: Clinical Science; 2/15/2024, Vol. 138 Issue 4, p173-187, 15p

مصطلحات موضوعية: ANTIOBESITY agents, WEIGHT loss, WESTERN diet, LEAN body mass, GASTRIC emptying

مستخلص: Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects. [ABSTRACT FROM AUTHOR]

: Copyright of Clinical Science is the property of Portland Press Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Byrne, Frances L., Olzomer, Ellen M., Lolies, Nina, Hoehn, Kyle L., Wegner, Marthe-Susanna

مصطلحات موضوعية: ddc:540, ddc:570, ddc:610

الوصف: Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer. Low numbers of HCC patients being suitable for liver resection or transplantation and multidrug resistance development during pharmacotherapy leads to high death rates for HCC patients. Understanding the molecular mechanisms of HCC etiology may contribute to the development of novel therapeutic strategies for prevention and treatment of HCC. UDP-glucose ceramide glycosyltransferase (UGCG), a key enzyme in glycosphingolipid metabolism, generates glucosylceramide (GlcCer), which is the precursor for all glycosphingolipids (GSLs). Since UGCG gene expression is altered in 0.8% of HCC tumors, GSLs may play a role in cellular processes in liver cancer cells. Here, we discuss the current literature about GSLs and their abundance in normal liver cells, Gaucher disease and HCC. Furthermore, we review the involvement of UGCG/GlcCer in multidrug resistance development, globosides as a potential prognostic marker for HCC, gangliosides as a potential liver cancer stem cell marker, and the role of sulfatides in tumor metastasis. Only a limited number of molecular mechanisms executed by GSLs in HCC are known, which we summarize here briefly. Overall, the role GSLs play in HCC progression and their ability to serve as biomarkers or prognostic indicators for HCC, requires further investigation.

وصف الملف: application/pdf

العلاقة: http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/80413Test; urn:nbn:de:hebis:30:3-804131; https://nbn-resolving.org/urn:nbn:de:hebis:30:3-804131Test; https://doi.org/10.3390/ijms23094477Test; http://publikationen.ub.uni-frankfurt.de/files/80413/ijms-23-04477.pdfTest

الإتاحة: https://doi.org/10.3390/ijms23094477Test
http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/80413Test
https://nbn-resolving.org/urn:nbn:de:hebis:30:3-804131Test
http://publikationen.ub.uni-frankfurt.de/files/80413/ijms-23-04477.pdfTest