Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis
Nonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver–alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insul...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2020-11-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1562 |
| _version_ | 1828043980990840832 |
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| author | Julie Steen Pedersen Marte Opseth Rygg Viggo Bjerregaard Kristiansen Beth Hærstedt Olsen Reza Rafiolsadat Serizawa Jens Juul Holst Sten Madsbad Lise Lotte Gluud Flemming Bendtsen Nicolai Jacob Wewer Albrechtsen |
| author_facet | Julie Steen Pedersen Marte Opseth Rygg Viggo Bjerregaard Kristiansen Beth Hærstedt Olsen Reza Rafiolsadat Serizawa Jens Juul Holst Sten Madsbad Lise Lotte Gluud Flemming Bendtsen Nicolai Jacob Wewer Albrechtsen |
| author_sort | Julie Steen Pedersen |
| collection | DOAJ |
| description | Nonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver–alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insulin resistance in individuals with obesity and whether bariatric surgery improves these parameters. Plasma and liver biopsies from 33 individuals with obesity (collectively, OBE) were obtained before and 12 months after bariatric surgery (Roux‐en‐Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). Nine healthy control individuals (collectively, CON) undergoing cholecystectomy were used as a comparison group. The NAFLD activity score (NAS) was used to subdivide study participants into the following groups: OBE‐no steatosis, OBE+steatosis, and nonalcoholic steatohepatitis (NASH) and/or grade 2 fibrosis (Fib) (OBE‐NASH‐Fib). Measurements of amino acids by targeted metabolomics and glucagon were performed. Glucagon, amino acids (P < 0.05), and the glucagon‐alanine index, a validated surrogate marker of glucagon resistance, were increased in OBE by 60%, 56%, and 61%, respectively, when compared with CON but irrespective of NAFLD severity. In contrast, markers of hepatic insulin resistance increased concomitantly with NAS. Hyperglucagonemia resolved in OBE‐no steatosis and OBE+steatosis but not in OBE‐NASH‐Fib (median, 7.0; interquartile range, 5.0‐9.8 pmol/L), regardless of improvement in insulin resistance and NAS. The type of surgery that participants underwent had no effect on metabolic outcomes. Conclusion: Glucagon resistance to amino acid metabolism exists in individuals with NAFLD independent of NAS severity. Patients with NASH showed persistent hyperglucagonemia 12 months after bariatric surgery, indicating that a disrupted liver–alpha cell may remain in NAFLD despite major improvement in liver histology. |
| first_indexed | 2024-04-10T17:49:44Z |
| format | Article |
| id | doaj.art-6fff59b9160d4d2ca277caf38894a653 |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-04-10T17:49:44Z |
| publishDate | 2020-11-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-6fff59b9160d4d2ca277caf38894a6532023-02-02T22:33:22ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2020-11-014111610162310.1002/hep4.1562Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and FibrosisJulie Steen Pedersen0Marte Opseth Rygg1Viggo Bjerregaard Kristiansen2Beth Hærstedt Olsen3Reza Rafiolsadat Serizawa4Jens Juul Holst5Sten Madsbad6Lise Lotte Gluud7Flemming Bendtsen8Nicolai Jacob Wewer Albrechtsen9Gastrounit Medical Division Copenhagen University Hospital Hvidovre Hvidovre DenmarkGastrounit Medical Division Copenhagen University Hospital Hvidovre Hvidovre DenmarkGastrounit Surgical Division Copenhagen University Hospital Hvidovre Hvidovre DenmarkDepartment of Nuclear Medicine and Functional Imaging, Ultrasound Section Copenhagen University Hospital Hvidovre Hvidovre DenmarkDepartment of Pathology Copenhagen University Hospital Hvidovre Hvidovre DenmarkDepartment of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen DenmarkDepartment of Endocrinology Copenhagen University Hospital Hvidovre Hvidovre DenmarkGastrounit Medical Division Copenhagen University Hospital Hvidovre Hvidovre DenmarkGastrounit Medical Division Copenhagen University Hospital Hvidovre Hvidovre DenmarkDepartment of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen DenmarkNonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver–alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insulin resistance in individuals with obesity and whether bariatric surgery improves these parameters. Plasma and liver biopsies from 33 individuals with obesity (collectively, OBE) were obtained before and 12 months after bariatric surgery (Roux‐en‐Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). Nine healthy control individuals (collectively, CON) undergoing cholecystectomy were used as a comparison group. The NAFLD activity score (NAS) was used to subdivide study participants into the following groups: OBE‐no steatosis, OBE+steatosis, and nonalcoholic steatohepatitis (NASH) and/or grade 2 fibrosis (Fib) (OBE‐NASH‐Fib). Measurements of amino acids by targeted metabolomics and glucagon were performed. Glucagon, amino acids (P < 0.05), and the glucagon‐alanine index, a validated surrogate marker of glucagon resistance, were increased in OBE by 60%, 56%, and 61%, respectively, when compared with CON but irrespective of NAFLD severity. In contrast, markers of hepatic insulin resistance increased concomitantly with NAS. Hyperglucagonemia resolved in OBE‐no steatosis and OBE+steatosis but not in OBE‐NASH‐Fib (median, 7.0; interquartile range, 5.0‐9.8 pmol/L), regardless of improvement in insulin resistance and NAS. The type of surgery that participants underwent had no effect on metabolic outcomes. Conclusion: Glucagon resistance to amino acid metabolism exists in individuals with NAFLD independent of NAS severity. Patients with NASH showed persistent hyperglucagonemia 12 months after bariatric surgery, indicating that a disrupted liver–alpha cell may remain in NAFLD despite major improvement in liver histology.https://doi.org/10.1002/hep4.1562 |
| spellingShingle | Julie Steen Pedersen Marte Opseth Rygg Viggo Bjerregaard Kristiansen Beth Hærstedt Olsen Reza Rafiolsadat Serizawa Jens Juul Holst Sten Madsbad Lise Lotte Gluud Flemming Bendtsen Nicolai Jacob Wewer Albrechtsen Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis Hepatology Communications |
| title | Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis |
| title_full | Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis |
| title_fullStr | Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis |
| title_full_unstemmed | Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis |
| title_short | Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis |
| title_sort | nonalcoholic fatty liver disease impairs the liver alpha cell axis independent of hepatic inflammation and fibrosis |
| url | https://doi.org/10.1002/hep4.1562 |
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