Open this publication in new window or tab >>Ataturk Univ, Vet Fac, Dept Pathol, Erzurum, Turkiye..
Ataturk Univ, Fac Med, Dept Med Pharmacol, Erzurum, Turkiye..
Ataturk Univ, Vet Fac, Dept Pathol, Erzurum, Turkiye..
Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, Erzurum, Turkiye..
Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, Erzurum, Turkiye..
Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, Erzurum, Turkiye..
Ataturk Univ, Vet Fac, Dept Pathol, Erzurum, Turkiye..
Trustlife Labs Drug Res & Dev Ctr, Istanbul, Turkiye..
Trustlife Labs Drug Res & Dev Ctr, Istanbul, Turkiye..
Ataturk Univ, Fac Med, Dept Med Pharmacol, Erzurum, Turkiye..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden..
Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkiye..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London, England..
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2025 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 13, article id RP98427Article in journal (Refereed) Published
Abstract [en]
Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.
Place, publisher, year, edition, pages
eLife Sciences Publications, Ltd, 2025
Keywords
MAFLD, JNK, sucrose, JNK-IN-5A, multi-tissue transcriptome, Rat
National Category
Basic Medicine
Identifiers
urn:nbn:se:kth:diva-360435 (URN)10.7554/eLife.98427 (DOI)001420073300001 ()39932177 (PubMedID)2-s2.0-85218435359 (Scopus ID)
Note
QC 20250303
2025-02-262025-02-262025-03-03Bibliographically approved