Nature communications, 2018-08, Vol.9 (1), p.3404-14, Article 3404
2018
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- Autor(en) / Beteiligte
- Titel
- Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation
- Ist Teil von
- Nature communications, 2018-08, Vol.9 (1), p.3404-14, Article 3404
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- AMP-activated protein kinase (AMPK) plays a key role in controlling energy metabolism in response to physiological and nutritional status. Although AMPK activation has been proposed as a promising molecular target for treating obesity and its related comorbidities, the use of pharmacological AMPK activators has been met with contradictory therapeutic challenges. Here we show a regulatory mechanism for AMPK through its ubiquitination and degradation by the E3 ubiquitin ligase makorin ring finger protein 1 (MKRN1). MKRN1 depletion promotes glucose consumption and suppresses lipid accumulation due to AMPK stabilisation and activation. Accordingly, MKRN1 -null mice show chronic AMPK activation in both liver and adipose tissue, resulting in significant suppression of diet-induced metabolic syndrome. We demonstrate also its therapeutic effect by administering shRNA targeting MKRN1 into obese mice that reverses non-alcoholic fatty liver disease. We suggest that ubiquitin-dependent AMPK degradation represents a target therapeutic strategy for metabolic disorders. AMPK activation has been suggested as treatment for obesity and its complications. Here the authors show that the ubiquitin ligase MKRN1 binds to AMPK and mediates its ubiquitination and degradation. Loss of MKRN1 leads to AMPK activation, increased glucose consumption and decreased lipid accumulation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-018-05721-4Titel-ID: cdi_doaj_primary_oai_doaj_org_article_808f9e7ecce2423aa60cf5a7715788c6
- Format
- –
- Schlagworte
- 13, 13/1, 13/105, 13/109, 13/31, 13/44, 13/51, 13/89, 42, 42/41, 42/44, 42/89, 631/337/458/582, 631/443/319/1642/2037, 631/443/319/1642/393, 82/58, Adipocytes - metabolism, Adipocytes - pathology, Adipose tissue, AMP, AMP-activated protein kinase, AMP-Activated Protein Kinases - genetics, AMP-Activated Protein Kinases - metabolism, Animals, Degradation, Diet, Diet, High-Fat - adverse effects, Energy metabolism, Fatty liver, Fatty Liver - genetics, Fatty Liver - metabolism, Female, Humanities and Social Sciences, Kinases, Liver, Liver - metabolism, Liver - pathology, Liver diseases, Male, Metabolic rate, Metabolic syndrome, Metabolic Syndrome - genetics, Metabolic Syndrome - metabolism, Metabolism, Mice, Mice, Knockout, multidisciplinary, Non-alcoholic Fatty Liver Disease - etiology, Non-alcoholic Fatty Liver Disease - metabolism, Nutritional status, Obesity, Pharmacology, Phosphates, Proteins, Regulatory mechanisms (biology), Ribonucleoproteins - genetics, Ribonucleoproteins - metabolism, Science, Science (multidisciplinary), Ubiquitin, Ubiquitin-protein ligase, Ubiquitin-Protein Ligases - genetics, Ubiquitin-Protein Ligases - metabolism, Ubiquitination