Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseases
Metabolic zonation in the liver carries out the maintenance of organ and body homeostasis. Hypoxia is an inherent physiological feature of the liver and contributes to the zonal properties of the hepatic parenchyma. As a master regulator of hypoxia, the transcription factor hypoxia-inducing factor (...
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| Format: | Article |
| Language: | English |
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Open Exploration Publishing Inc.
2022-12-01
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| Series: | Exploration of Digestive Diseases |
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| Online Access: | https://www.explorationpub.com/Journals/edd/Article/100512 |
| _version_ | 1797845394771673088 |
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| author | Sandra Torres Jose C. Fernandez-Checa Carmen Garcia-Ruiz |
| author_facet | Sandra Torres Jose C. Fernandez-Checa Carmen Garcia-Ruiz |
| author_sort | Sandra Torres |
| collection | DOAJ |
| description | Metabolic zonation in the liver carries out the maintenance of organ and body homeostasis. Hypoxia is an inherent physiological feature of the liver and contributes to the zonal properties of the hepatic parenchyma. As a master regulator of hypoxia, the transcription factor hypoxia-inducing factor (HIF) is stabilized primarily by oxygen availability, and it is thought to contribute to steatohepatitis due to alcohol-related (ASH) and non-alcohol-related liver disease (NASH). Cholesterol has emerged as an important player in both diseases, and hypoxia increases hepatic cholesterol levels. Steroidogenic acute regulatory protein 1 (STARD1) is a mitochondrial outer membrane protein that transfers cholesterol to mitochondrial inner membrane for metabolic processing and acts as the rate-limiting step in the alternative pathway of bile acid synthesis in hepatocytes. STARD1 expression increases in ASH and NASH and determines the accumulation of cholesterol in mitochondria, which impacts the physico-chemical mitochondrial membranes properties and as a consequence impairs the activity of specific mitochondrial solute carriers, such as the 2-oxoglutarate carrier (2-OGC), limiting the exchange between cytosolic glutathione and mitochondrial 2-oxoglutarate (2-OG). Although HIF-1 is stabilized in hypoxia largely due to the requirement of prolylhydroxylases (PHDs) for oxygen to signal HIF degradation, PHDs are also dependent on 2-OG, and therefore it is conceivable that impairment of 2-OGC by STARD1-mediated cholesterol accumulation may contribute to HIF-1 stabilization due in part to decreased availability of cytosolic 2-OG. In this perspective, this review explores the interplay between HIF-1 stabilization and STARD1 induction and the potential contribution of this functional relationship to ASH and NASH. |
| first_indexed | 2024-04-09T17:38:21Z |
| format | Article |
| id | doaj.art-442f365f1eff431783814ad73be81c8a |
| institution | Directory Open Access Journal |
| issn | 2833-6321 |
| language | English |
| last_indexed | 2024-04-09T17:38:21Z |
| publishDate | 2022-12-01 |
| publisher | Open Exploration Publishing Inc. |
| record_format | Article |
| series | Exploration of Digestive Diseases |
| spelling | doaj.art-442f365f1eff431783814ad73be81c8a2023-04-17T08:08:39ZengOpen Exploration Publishing Inc.Exploration of Digestive Diseases2833-63212022-12-0113170186https://doi.org/10.37349/edd.2022.00012Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseasesSandra Torres0https://orcid.org/0000-0002-2894-3188Jose C. Fernandez-Checa1https://orcid.org/0000-0003-3422-2990Carmen Garcia-Ruiz2https://orcid.org/0000-0002-2652-6102Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, SpainDepartment of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USDepartment of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USMetabolic zonation in the liver carries out the maintenance of organ and body homeostasis. Hypoxia is an inherent physiological feature of the liver and contributes to the zonal properties of the hepatic parenchyma. As a master regulator of hypoxia, the transcription factor hypoxia-inducing factor (HIF) is stabilized primarily by oxygen availability, and it is thought to contribute to steatohepatitis due to alcohol-related (ASH) and non-alcohol-related liver disease (NASH). Cholesterol has emerged as an important player in both diseases, and hypoxia increases hepatic cholesterol levels. Steroidogenic acute regulatory protein 1 (STARD1) is a mitochondrial outer membrane protein that transfers cholesterol to mitochondrial inner membrane for metabolic processing and acts as the rate-limiting step in the alternative pathway of bile acid synthesis in hepatocytes. STARD1 expression increases in ASH and NASH and determines the accumulation of cholesterol in mitochondria, which impacts the physico-chemical mitochondrial membranes properties and as a consequence impairs the activity of specific mitochondrial solute carriers, such as the 2-oxoglutarate carrier (2-OGC), limiting the exchange between cytosolic glutathione and mitochondrial 2-oxoglutarate (2-OG). Although HIF-1 is stabilized in hypoxia largely due to the requirement of prolylhydroxylases (PHDs) for oxygen to signal HIF degradation, PHDs are also dependent on 2-OG, and therefore it is conceivable that impairment of 2-OGC by STARD1-mediated cholesterol accumulation may contribute to HIF-1 stabilization due in part to decreased availability of cytosolic 2-OG. In this perspective, this review explores the interplay between HIF-1 stabilization and STARD1 induction and the potential contribution of this functional relationship to ASH and NASH.https://www.explorationpub.com/Journals/edd/Article/100512hypoxiacholesterol transportmitochondriareactive oxygen species |
| spellingShingle | Sandra Torres Jose C. Fernandez-Checa Carmen Garcia-Ruiz Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseases Exploration of Digestive Diseases hypoxia cholesterol transport mitochondria reactive oxygen species |
| title | Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseases |
| title_full | Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseases |
| title_fullStr | Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseases |
| title_full_unstemmed | Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseases |
| title_short | Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseases |
| title_sort | hypoxia signaling and cholesterol steroidogenic acute regulatory protein 1 axis interplay and role in alcohol and non alcohol related liver diseases |
| topic | hypoxia cholesterol transport mitochondria reactive oxygen species |
| url | https://www.explorationpub.com/Journals/edd/Article/100512 |
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