The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach
The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative st...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Current Issues in Molecular Biology |
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| Online Access: | https://www.mdpi.com/1467-3045/45/11/570 |
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| author | Milena Vesković Nikola Šutulović Dragan Hrnčić Olivera Stanojlović Djuro Macut Dušan Mladenović |
| author_facet | Milena Vesković Nikola Šutulović Dragan Hrnčić Olivera Stanojlović Djuro Macut Dušan Mladenović |
| author_sort | Milena Vesković |
| collection | DOAJ |
| description | The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression. |
| first_indexed | 2024-03-09T16:55:43Z |
| format | Article |
| id | doaj.art-5e043753ddca4a9689d134b688507f38 |
| institution | Directory Open Access Journal |
| issn | 1467-3037 1467-3045 |
| language | English |
| last_indexed | 2024-03-09T16:55:43Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Issues in Molecular Biology |
| spelling | doaj.art-5e043753ddca4a9689d134b688507f382023-11-24T14:36:10ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452023-11-0145119084910210.3390/cimb45110570The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric ApproachMilena Vesković0Nikola Šutulović1Dragan Hrnčić2Olivera Stanojlović3Djuro Macut4Dušan Mladenović5Institute of Pathophysiology “Ljubodrag Buba Mihailovic”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaInstitute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaInstitute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaInstitute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaClinic of Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaInstitute of Pathophysiology “Ljubodrag Buba Mihailovic”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaThe central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.https://www.mdpi.com/1467-3045/45/11/570insulin resistanceNAFLDhepatokinesER stresscircadian clocklow-grade inflammation |
| spellingShingle | Milena Vesković Nikola Šutulović Dragan Hrnčić Olivera Stanojlović Djuro Macut Dušan Mladenović The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach Current Issues in Molecular Biology insulin resistance NAFLD hepatokines ER stress circadian clock low-grade inflammation |
| title | The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach |
| title_full | The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach |
| title_fullStr | The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach |
| title_full_unstemmed | The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach |
| title_short | The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach |
| title_sort | interconnection between hepatic insulin resistance and metabolic dysfunction associated steatotic liver disease the transition from an adipocentric to liver centric approach |
| topic | insulin resistance NAFLD hepatokines ER stress circadian clock low-grade inflammation |
| url | https://www.mdpi.com/1467-3045/45/11/570 |
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