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7. Silencing of STE20-type kinase TAOK1 confers protection against hepatocellular lipotoxicity through metabolic rewiring

Author

Xia, Ying, primary, Andersson, Emma, additional, Anand, Sumit K., additional, Cansby, Emmelie, additional, Caputo, Mara, additional, Kumari, Sima, additional, Porosk, Rando, additional, Kilk, Kalle, additional, Nair, Syam, additional, Marschall, Hanns-Ulrich, additional, Blüher, Matthias, additional, and Mahlapuu, Margit, additional

Published
2023
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11. Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage

Author

Anand, Sumit Kumar, primary, Caputo, Mara, additional, Xia, Ying, additional, Andersson, Emma, additional, Cansby, Emmelie, additional, Kumari, Sima, additional, Henricsson, Marcus, additional, Porosk, Rando, additional, Keuenhof, Katharina Susanne, additional, Höög, Johanna Louise, additional, Nair, Syam, additional, Marschall, Hanns-Ulrich, additional, Blüher, Matthias, additional, and Mahlapuu, Margit, additional

Published
2022
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17. Silencing of STE20‐type kinase MST3 in mice with antisense oligonucleotide treatment ameliorates diet‐induced nonalcoholic fatty liver disease

Author

Caputo, Mara, primary, Kurhe, Yeshwant, additional, Kumari, Sima, additional, Cansby, Emmelie, additional, Amrutkar, Manoj, additional, Scandalis, Eli, additional, Booten, Sheri L., additional, Ståhlman, Marcus, additional, Borén, Jan, additional, Marschall, Hanns‐Ulrich, additional, Aghajan, Mariam, additional, and Mahlapuu, Margit, additional

Published
2021
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18. STE20 ‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes

Author

Caputo, Mara, primary, Cansby, Emmelie, additional, Kumari, Sima, additional, Kurhe, Yeshwant, additional, Nair, Syam, additional, Ståhlman, Marcus, additional, Kulkarni, Nagaraj M., additional, Borén, Jan, additional, Marschall, Hanns‐Ulrich, additional, Blüher, Matthias, additional, and Mahlapuu, Margit, additional

Published
2021
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19. Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease

Author

Cansby, Emmelie, primary, Caputo, Mara, additional, Gao, Lei, additional, Kulkarni, Nagaraj M., additional, Nerstedt, Annika, additional, Ståhlman, Marcus, additional, Borén, Jan, additional, Porosk, Rando, additional, Soomets, Ursel, additional, Pedrelli, Matteo, additional, Parini, Paolo, additional, Marschall, Hanns-Ulrich, additional, Nyström, Jenny, additional, Howell, Brian W., additional, and Mahlapuu, Margit, additional

Published
2020
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20. Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver

Author

Nerstedt, Annika, primary, Kurhe, Yeshwant, additional, Cansby, Emmelie, additional, Caputo, Mara, additional, Gao, Lei, additional, Vorontsov, Egor, additional, Ståhlman, Marcus, additional, Nuñez-Durán, Esther, additional, Borén, Jan, additional, Marschall, Hanns-Ulrich, additional, Mashek, Douglas G., additional, Saunders, Darren N., additional, Sihlbom, Carina, additional, Hoy, Andrew J., additional, and Mahlapuu, Margit, additional

Published
2020
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21. Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease

Author

Cansby, Emmelie, Nuñez-Durán, Esther, Magnusson, Elin, Amrutkar, Manoj, Booten, Sheri L., Kulkarni, Nagaraj M., Svensson, L. Thomas, Borén, Jan, Marschall, Hanns-Ulrich, Aghajan, Mariam, and Mahlapuu, Margit

Subjects
Male, Mice, Obese, Apoptosis, ACC, acetyl-CoA carboxylase, Mice, GalNAc, N-acetylgalactosamine, AST, aspartate transaminase, Non-alcoholic Fatty Liver Disease, Original Research, NASH, Intracellular Signaling Peptides and Proteins, WAT, white adipose tissue, Organ Size, TBARS, thiobarbituric acid-reactive substance, mRNA, messenger RNA, Mitochondria, Editorial, Hepatic Steatosis, Liver, Liver Fibrosis, NASH, nonalcoholic steatohepatitis, TAG, triacylglycerol, PCNA, proliferating cell nuclear antigen, PBS, phosphate-buffered saline, ASO, antisense oligonucleotide, Protein Serine-Threonine Kinases, Diet, High-Fat, ASGP, asialoglycoprotein, Acetylglucosamine, STK25, serine/threonine kinase 25, NAFLD, Antisense Oligonucleotide Therapy, 4-HNE, 4-hydroxynonenal, ALT, alanine aminotransferase, Animals, RNA, Messenger, ASOR, 125I-asialo-orosomucoid, Lipogenesis, Macrophages, Body Weight, Oligonucleotides, Antisense, STK25, serine/threonine protein kinase 25, digestive system diseases, Mice, Inbred C57BL, Oxidative Stress, Gene Expression Regulation, Hepatocytes, NAFLD, nonalcoholic fatty liver disease, DHE, dihydroethidium, NAS, nonalcoholic fatty liver disease activity score, Acetyl-CoA Carboxylase
Abstract

Background & Aims Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide. Currently, no specific pharmacologic therapy is available for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK)25 as a critical regulator of hepatic lipid partitioning and NAFLD/NASH. Here, we studied the metabolic benefit of liver-specific STK25 inhibitors on NAFLD development and progression in a mouse model of diet-induced obesity. Methods We developed a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) targeting Stk25 and evaluated its effect on NAFLD features in mice after chronic exposure to dietary lipids. Results We found that systemic administration of hepatocyte-targeting GalNAc-Stk25 ASO in obese mice effectively ameliorated steatosis, inflammatory infiltration, hepatic stellate cell activation, nutritional fibrosis, and hepatocellular damage in the liver compared with mice treated with GalNAc-conjugated nontargeting ASO, without any systemic toxicity or local tolerability concerns. We also observed protection against high-fat-diet–induced hepatic oxidative stress and improved mitochondrial function with Stk25 ASO treatment in mice. Moreover, GalNAc-Stk25 ASO suppressed lipogenic gene expression and acetyl-CoA carboxylase protein abundance in the liver, providing insight into the molecular mechanisms underlying repression of hepatic steatosis. Conclusions This study provides in vivo nonclinical proof-of-principle for the metabolic benefit of liver-specific inhibition of STK25 in the context of obesity and warrants future investigations to address the therapeutic potential of GalNAc-Stk25 ASO in the prevention and treatment of NAFLD., Graphical abstract

Published
2018

22. Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

Author

Cansby, Emmelie, primary, Kulkarni, Nagaraj M., additional, Magnusson, Elin, additional, Kurhe, Yeshwant, additional, Amrutkar, Manoj, additional, Nerstedt, Annika, additional, Ståhlman, Marcus, additional, Sihlbom, Carina, additional, Marschall, Hanns‐Ulrich, additional, Borén, Jan, additional, Blüher, Matthias, additional, and Mahlapuu, And Margit, additional

Published
2019
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23. STK25 regulates oxidative capacity and metabolic efficiency in adipose tissue

Author

Sütt, Silva, primary, Cansby, Emmelie, additional, Paul, Alexandra, additional, Amrutkar, Manoj, additional, Nuñez-Durán, Esther, additional, Kulkarni, Nagaraj M, additional, Ståhlman, Marcus, additional, Borén, Jan, additional, Laurencikiene, Jurga, additional, Howell, Brian W, additional, Enerbäck, Sven, additional, and Mahlapuu, Margit, additional

Published
2018
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24. Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice

Author

Nuñez‐Durán, Esther, primary, Aghajan, Mariam, additional, Amrutkar, Manoj, additional, Sütt, Silva, additional, Cansby, Emmelie, additional, Booten, Sheri L., additional, Watt, Andrew, additional, Ståhlman, Marcus, additional, Stefan, Norbert, additional, Häring, Hans‐Ulrich, additional, Staiger, Harald, additional, Borén, Jan, additional, Marschall, Hanns‐Ulrich, additional, and Mahlapuu, Margit, additional

Published
2017
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26. Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle

Author

Chursa, Urszula, primary, Nuñez-Durán, Esther, additional, Cansby, Emmelie, additional, Amrutkar, Manoj, additional, Sütt, Silva, additional, Ståhlman, Marcus, additional, Olsson, Britt-Marie, additional, Borén, Jan, additional, Johansson, Maria E., additional, Bäckhed, Fredrik, additional, Johansson, Bengt R., additional, Sihlbom, Carina, additional, and Mahlapuu, Margit, additional

Published
2016
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27. Regulation of metabolism and inflammation by two protein kinases - AMPK and STK25

Author

Cansby, Emmelie

Subjects
AMPK, Inflammation, Metabolism, STK25, Type 2 diabetes
Abstract

Type 2 diabetes mellitus (T2DM) is a widespread metabolic disorder that has reached epidemic proportions globally, and is now considered to be one of the main threats to human health. The currently available treatment options in T2DM suffer from inadequate efficacy and durability, as well as liabilities, including hypoglycemia, weight gain, edema and gastrointestinal intolerance. Since the efficacy and patient compliance of existing treatments are in many cases unsatisfactory, there is a pronounced need for novel targets, which could complement current treatment. Evidence accumulated during the last two decades indicates that excessive caloric intake and obesity lead to a chronic low-grade inflammation in metabolic tissues, and increased inflammation may be directly involved in the pathogenesis of T2DM. Therefore, novel pharmacological treatments targeting both the metabolic and inflammatory disruptions seen in T2DM are warranted. AMP-activated protein kinase (AMPK) is a central master switch important for regulating energy homeostasis at cellular as well as whole body level. Recently, evidence for a role of AMPK in regulation of inflammatory balance has emerged. By using AMPK agonists AICAR and metformin in liver cell lines, primary hepatocytes and in mouse model system in vivo, we demonstrate that AMPK activation in liver leads to decreased inflammatory response to the proinflammatory cytokine IL-6. We further show that the anti-inflammatory action of AMPK was mediated via decreased phosphorylation of several downstream components of the canonical IL-6 receptor signalling pathway. Inhibition of the IL-6 signalling cascade in liver by AMPK supports a role of this kinase as a crucial point of convergence of metabolic and inflammatory pathways in hepatocytes. Serine/threonine protein kinase 25 (STK25) is broadly expressed in mouse, rat and human tissues. When activated, this kinase is part of several cell processes, such as development, migration and apoptosis. We, for the first time, show that STK25 also has metabolic effects. By using small interfering RNA for Stk25 in rodent muscle cell line L6, we demonstrate that STK25 is involved in regulation of glucose uptake and lipid oxidation. Furthermore, mice overexpressing STK25, when challenged with a high-fat diet, develop reduced glucose tolerance and insulin sensitivity compared to wild-type siblings. Increased triglyceride deposition in liver and skeletal muscle, and adipocyte hypertrophy, as observed in Stk25 transgenic mice, suggest that the underlying cause of insulin resistance in conditions of excess dietary fuels is a shift in the metabolic balance from lipid oxidation toward lipid storage in peripheral tissues. Furthermore, Stk25 transgenic mice show increased infiltration of inflammatory cells in liver. Taken together, both AMPK and STK25 emerge as interesting targets for future treatment of T2DM, enabling to target the dysregulation of both metabolism and inflammation seen in connection with this disease.

Published
2014

29. Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice.

Author

Nuñez‐Durán, Esther, Aghajan, Mariam, Amrutkar, Manoj, Sütt, Silva, Cansby, Emmelie, Booten, Sheri L., Watt, Andrew, Ståhlman, Marcus, Stefan, Norbert, Häring, Hans‐Ulrich, Staiger, Harald, Borén, Jan, Marschall, Hanns‐Ulrich, and Mahlapuu, Margit

Subjects
SERINE/THREONINE kinases, FATTY liver, TYPE 2 diabetes
Abstract

Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty‐first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting Stk25 on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that Stk25 ASOs efficiently reversed high‐fat diet‐induced systemic hyperglycemia and hyperinsulinemia, improved whole‐body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, Stk25 ASOs suppressed the abundance of liver acetyl‐coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single‐nucleotide polymorphisms in the human STK25 gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. Conclusion: Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. (Hepatology Communications 2018;2:69–83) [ABSTRACT FROM AUTHOR]

Published
2018
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33. Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high‐fat diet

Author

Cansby, Emmelie, primary, Amrutkar, Manoj, additional, Holm, Louise Mannerås, additional, Nerstedt, Annika, additional, Reyahi, Azadeh, additional, Stenfeldt, Elin, additional, Borén, Jan, additional, Carlsson, Peter, additional, Smith, Ulf, additional, Zierath, Juleen R., additional, and Mahlapuu, Margit, additional

Published
2013
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