Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo
Objective: Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is a...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823001011 |
| _version_ | 1797755025024352256 |
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| author | Sandip Mukherjee Molee Chakraborty Eliwaza N. Msengi Jake Haubner Jinsong Zhang Matthew J. Jellinek Haley L. Carlson Kelly Pyles Barbara Ulmasov Andrew J. Lutkewitte Danielle Carpenter Kyle S. McCommis David A. Ford Brian N. Finck Brent A. Neuschwander-Tetri Anutosh Chakraborty |
| author_facet | Sandip Mukherjee Molee Chakraborty Eliwaza N. Msengi Jake Haubner Jinsong Zhang Matthew J. Jellinek Haley L. Carlson Kelly Pyles Barbara Ulmasov Andrew J. Lutkewitte Danielle Carpenter Kyle S. McCommis David A. Ford Brian N. Finck Brent A. Neuschwander-Tetri Anutosh Chakraborty |
| author_sort | Sandip Mukherjee |
| collection | DOAJ |
| description | Objective: Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer. However, its in vivo function is unknown, and no animal models are available to study this novel protein. Methods: A whole-body Ube4A knockout (UKO) mouse model was generated, and various metabolic parameters were compared in chow- and high fat diet (HFD)-fed WT and UKO mice, and in their liver, adipose tissue, and serum. Lipidomics and RNA-Seq studies were performed in the liver samples of HFD-fed WT and UKO mice. Proteomic studies were conducted to identify Ube4A's targets in metabolism. Furthermore, a mechanism by which Ube4A regulates metabolism was identified. Results: Although the body weight and composition of young, chow-fed WT and UKO mice are similar, the knockouts exhibit mild hyperinsulinemia and insulin resistance. HFD feeding substantially augments obesity, hyperinsulinemia, and insulin resistance in both sexes of UKO mice. HFD-fed white and brown adipose tissue depots of UKO mice have increased insulin resistance and inflammation and reduced energy metabolism. Moreover, Ube4A deletion exacerbates hepatic steatosis, inflammation, and liver injury in HFD-fed mice with increased lipid uptake and lipogenesis in hepatocytes. Acute insulin treatment resulted in impaired activation of the insulin effector protein kinase Akt in liver and adipose tissue of chow-fed UKO mice. We identified the Akt activator protein APPL1 as a Ube4A interactor. The K63-linked ubiquitination (K63-Ub) of Akt and APPL1, known to facilitate insulin-induced Akt activation, is impaired in UKO mice. Furthermore, Ube4A K63-ubiquitinates Akt in vitro. Conclusion: Ube4A is a novel regulator of obesity, insulin resistance, adipose tissue dysfunction and NAFLD, and preventing its downregulation may ameliorate these diseases. |
| first_indexed | 2024-03-12T17:41:58Z |
| format | Article |
| id | doaj.art-b2642d46704a4c24822cb884661aab61 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-12T17:41:58Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-b2642d46704a4c24822cb884661aab612023-08-04T05:47:34ZengElsevierMolecular Metabolism2212-87782023-09-0175101767Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivoSandip Mukherjee0Molee Chakraborty1Eliwaza N. Msengi2Jake Haubner3Jinsong Zhang4Matthew J. Jellinek5Haley L. Carlson6Kelly Pyles7Barbara Ulmasov8Andrew J. Lutkewitte9Danielle Carpenter10Kyle S. McCommis11David A. Ford12Brian N. Finck13Brent A. Neuschwander-Tetri14Anutosh Chakraborty15Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADivision of Gastroenterology and Hepatology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADivision of Geriatrics and Nutritional Science, Washington University School of Medicine, Saint Louis, MO, 63110, USADepartment of Pathology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADivision of Geriatrics and Nutritional Science, Washington University School of Medicine, Saint Louis, MO, 63110, USADivision of Gastroenterology and Hepatology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA; Corresponding author. Saint Louis University School of Medicine, Department of Pharmacology and Physiology, M370, Schwitalla Hall, 1402 South Grand Blvd, Saint Louis, Missouri, 63104, USA.Objective: Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer. However, its in vivo function is unknown, and no animal models are available to study this novel protein. Methods: A whole-body Ube4A knockout (UKO) mouse model was generated, and various metabolic parameters were compared in chow- and high fat diet (HFD)-fed WT and UKO mice, and in their liver, adipose tissue, and serum. Lipidomics and RNA-Seq studies were performed in the liver samples of HFD-fed WT and UKO mice. Proteomic studies were conducted to identify Ube4A's targets in metabolism. Furthermore, a mechanism by which Ube4A regulates metabolism was identified. Results: Although the body weight and composition of young, chow-fed WT and UKO mice are similar, the knockouts exhibit mild hyperinsulinemia and insulin resistance. HFD feeding substantially augments obesity, hyperinsulinemia, and insulin resistance in both sexes of UKO mice. HFD-fed white and brown adipose tissue depots of UKO mice have increased insulin resistance and inflammation and reduced energy metabolism. Moreover, Ube4A deletion exacerbates hepatic steatosis, inflammation, and liver injury in HFD-fed mice with increased lipid uptake and lipogenesis in hepatocytes. Acute insulin treatment resulted in impaired activation of the insulin effector protein kinase Akt in liver and adipose tissue of chow-fed UKO mice. We identified the Akt activator protein APPL1 as a Ube4A interactor. The K63-linked ubiquitination (K63-Ub) of Akt and APPL1, known to facilitate insulin-induced Akt activation, is impaired in UKO mice. Furthermore, Ube4A K63-ubiquitinates Akt in vitro. Conclusion: Ube4A is a novel regulator of obesity, insulin resistance, adipose tissue dysfunction and NAFLD, and preventing its downregulation may ameliorate these diseases.http://www.sciencedirect.com/science/article/pii/S2212877823001011Ube4AUbiquitinationObesityNAFLDInsulin/Akt signalingAPPL1 |
| spellingShingle | Sandip Mukherjee Molee Chakraborty Eliwaza N. Msengi Jake Haubner Jinsong Zhang Matthew J. Jellinek Haley L. Carlson Kelly Pyles Barbara Ulmasov Andrew J. Lutkewitte Danielle Carpenter Kyle S. McCommis David A. Ford Brian N. Finck Brent A. Neuschwander-Tetri Anutosh Chakraborty Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo Molecular Metabolism Ube4A Ubiquitination Obesity NAFLD Insulin/Akt signaling APPL1 |
| title | Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo |
| title_full | Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo |
| title_fullStr | Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo |
| title_full_unstemmed | Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo |
| title_short | Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo |
| title_sort | ube4a maintains metabolic homeostasis and facilitates insulin signaling in vivo |
| topic | Ube4A Ubiquitination Obesity NAFLD Insulin/Akt signaling APPL1 |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823001011 |
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