Short‐Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation
Abstract Statins, the first‐line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short‐term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of stat...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-09-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202403451 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850261811732938752 |
|---|---|
| author | Yijun Lin Shuying Wang Zixuan Li Yuling Zhou Ruiying Wang Yan Wang Yan Chen |
| author_facet | Yijun Lin Shuying Wang Zixuan Li Yuling Zhou Ruiying Wang Yan Wang Yan Chen |
| author_sort | Yijun Lin |
| collection | DOAJ |
| description | Abstract Statins, the first‐line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short‐term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of statin‐induced diabetes. Statin medication raises the expression of progesterone and adiponectin receptor 9 (PAQR9) in liver, which inhibits insulin signaling through degradation of protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α) to activate ERK pathway. STIP1 homology and U‐box containing protein 1 (STUB1) is found to mediate ubiquitination of PPM1α promoted by PAQR9. On the other hand, decreased activity of hepatocyte nuclear factor 4 alpha (HNF4α) seems to be the cause of PAQR9 expression under statin therapy. The interventions on PAQR9, including deletion of PAQR9, caloric restriction and HNF4α activation, are all effective treatments for statin‐induced diabetes, while liver specific over‐expression of PPM1α is another possible tactic. The results reveal the importance of HNF4α‐PAQR9‐STUB1‐PPM1α axis in controlling the statin‐induced hepatic insulin resistance, offering a fresh insight into the molecular mechanisms underlying statin therapy. |
| format | Article |
| id | doaj-art-c508dd08f8d04ec8a47e1a7ff2910fb8 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-c508dd08f8d04ec8a47e1a7ff2910fb82025-08-20T01:55:19ZengWileyAdvanced Science2198-38442024-09-011134n/an/a10.1002/advs.202403451Short‐Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT PhosphorylationYijun Lin0Shuying Wang1Zixuan Li2Yuling Zhou3Ruiying Wang4Yan Wang5Yan Chen6Xiamen Cardiovascular Hospital School of Medicine Xiamen University Xiamen 361016 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaXiamen Cardiovascular Hospital School of Medicine Xiamen University Xiamen 361016 ChinaXiamen Cardiovascular Hospital School of Medicine Xiamen University Xiamen 361016 ChinaXiamen Cardiovascular Hospital School of Medicine Xiamen University Xiamen 361016 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaAbstract Statins, the first‐line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short‐term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of statin‐induced diabetes. Statin medication raises the expression of progesterone and adiponectin receptor 9 (PAQR9) in liver, which inhibits insulin signaling through degradation of protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α) to activate ERK pathway. STIP1 homology and U‐box containing protein 1 (STUB1) is found to mediate ubiquitination of PPM1α promoted by PAQR9. On the other hand, decreased activity of hepatocyte nuclear factor 4 alpha (HNF4α) seems to be the cause of PAQR9 expression under statin therapy. The interventions on PAQR9, including deletion of PAQR9, caloric restriction and HNF4α activation, are all effective treatments for statin‐induced diabetes, while liver specific over‐expression of PPM1α is another possible tactic. The results reveal the importance of HNF4α‐PAQR9‐STUB1‐PPM1α axis in controlling the statin‐induced hepatic insulin resistance, offering a fresh insight into the molecular mechanisms underlying statin therapy.https://doi.org/10.1002/advs.202403451AKT phosphorylationhepatic insulin resistanceprogesterone and adiponectin receptor 9 (PAQR9)statinstype 2 diabetes |
| spellingShingle | Yijun Lin Shuying Wang Zixuan Li Yuling Zhou Ruiying Wang Yan Wang Yan Chen Short‐Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation Advanced Science AKT phosphorylation hepatic insulin resistance progesterone and adiponectin receptor 9 (PAQR9) statins type 2 diabetes |
| title | Short‐Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation |
| title_full | Short‐Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation |
| title_fullStr | Short‐Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation |
| title_full_unstemmed | Short‐Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation |
| title_short | Short‐Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation |
| title_sort | short term statin therapy induces hepatic insulin resistance through hnf4α paqr9 ppm1α axis regulated akt phosphorylation |
| topic | AKT phosphorylation hepatic insulin resistance progesterone and adiponectin receptor 9 (PAQR9) statins type 2 diabetes |
| url | https://doi.org/10.1002/advs.202403451 |
| work_keys_str_mv | AT yijunlin shorttermstatintherapyinduceshepaticinsulinresistancethroughhnf4apaqr9ppm1aaxisregulatedaktphosphorylation AT shuyingwang shorttermstatintherapyinduceshepaticinsulinresistancethroughhnf4apaqr9ppm1aaxisregulatedaktphosphorylation AT zixuanli shorttermstatintherapyinduceshepaticinsulinresistancethroughhnf4apaqr9ppm1aaxisregulatedaktphosphorylation AT yulingzhou shorttermstatintherapyinduceshepaticinsulinresistancethroughhnf4apaqr9ppm1aaxisregulatedaktphosphorylation AT ruiyingwang shorttermstatintherapyinduceshepaticinsulinresistancethroughhnf4apaqr9ppm1aaxisregulatedaktphosphorylation AT yanwang shorttermstatintherapyinduceshepaticinsulinresistancethroughhnf4apaqr9ppm1aaxisregulatedaktphosphorylation AT yanchen shorttermstatintherapyinduceshepaticinsulinresistancethroughhnf4apaqr9ppm1aaxisregulatedaktphosphorylation |