Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents
Objective: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously f...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823001473 |
| _version_ | 1797454346849353728 |
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| author | Chunxue Zhou Henry H. Ruiz Li Ling Giulia Maurizi Kenichi Sakamoto Claudia G. Liberini Ling Wang Adrien Stanley Hale E. Egritag Sofia M. Sanz Claudia Lindtner Mary A. Butera Christoph Buettner |
| author_facet | Chunxue Zhou Henry H. Ruiz Li Ling Giulia Maurizi Kenichi Sakamoto Claudia G. Liberini Ling Wang Adrien Stanley Hale E. Egritag Sofia M. Sanz Claudia Lindtner Mary A. Butera Christoph Buettner |
| author_sort | Chunxue Zhou |
| collection | DOAJ |
| description | Objective: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain–SNS–adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. Methods: We examined the role of lipolysis, and the brain–SNS–adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1β (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with β3 adrenergic agonist or undergoing restraint stress. Results: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through β3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. Conclusions: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD. |
| first_indexed | 2024-03-09T15:35:58Z |
| format | Article |
| id | doaj.art-592fa73d8ff24ad284823221a6a6e218 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-09T15:35:58Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-592fa73d8ff24ad284823221a6a6e2182023-11-26T05:12:28ZengElsevierMolecular Metabolism2212-87782023-12-0178101813Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodentsChunxue Zhou0Henry H. Ruiz1Li Ling2Giulia Maurizi3Kenichi Sakamoto4Claudia G. Liberini5Ling Wang6Adrien Stanley7Hale E. Egritag8Sofia M. Sanz9Claudia Lindtner10Mary A. Butera11Christoph Buettner12Department of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Endocrinology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Endocrinology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USADepartment of Medicine and Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Endocrinology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Corresponding author. Clinical Academic Building, Rm 7204, Rutgers The State University of New Jersey, 125 Paterson Street, New Brunswick, NJ 08901-1962, USA.Objective: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain–SNS–adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. Methods: We examined the role of lipolysis, and the brain–SNS–adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1β (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with β3 adrenergic agonist or undergoing restraint stress. Results: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through β3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. Conclusions: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.http://www.sciencedirect.com/science/article/pii/S2212877823001473Sympathetic outflowAdipose triglyceride lipaseTyrosine hydroxylaseβ3 adrenergic agonismInsulin signaling |
| spellingShingle | Chunxue Zhou Henry H. Ruiz Li Ling Giulia Maurizi Kenichi Sakamoto Claudia G. Liberini Ling Wang Adrien Stanley Hale E. Egritag Sofia M. Sanz Claudia Lindtner Mary A. Butera Christoph Buettner Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents Molecular Metabolism Sympathetic outflow Adipose triglyceride lipase Tyrosine hydroxylase β3 adrenergic agonism Insulin signaling |
| title | Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents |
| title_full | Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents |
| title_fullStr | Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents |
| title_full_unstemmed | Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents |
| title_short | Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents |
| title_sort | sympathetic overdrive and unrestrained adipose lipolysis drive alcohol induced hepatic steatosis in rodents |
| topic | Sympathetic outflow Adipose triglyceride lipase Tyrosine hydroxylase β3 adrenergic agonism Insulin signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823001473 |
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