The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease
Abstract Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-04-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02202-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850202331771043840 |
|---|---|
| author | Chandana Thimme Gowda Mallikarjuna Siraganahalli Eshwaraiah Jiaohong Wang Youngyi Lim Maria Lauda Tomasi Nirmala Mavila Komal Ramani |
| author_facet | Chandana Thimme Gowda Mallikarjuna Siraganahalli Eshwaraiah Jiaohong Wang Youngyi Lim Maria Lauda Tomasi Nirmala Mavila Komal Ramani |
| author_sort | Chandana Thimme Gowda |
| collection | DOAJ |
| description | Abstract Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation (FAO). The goal of this work is to examine how AKAP12’s PKA-anchoring ability regulates outcomes of alcohol-associated steatosis. Crosslinking proteomics identified PKA and its lipogenic substrates as interacting partners of AKAP12. Alcohol exposure diminished AKAP12’s interaction with PKA regulatory subunits and PKA substrates, acetyl CoA carboxylase (ACC1), pyruvate dehydrogenase (PDHA) and adipose triglyceride lipase (ATGL). Alcohol inhibited PKA activity and increased triglyceride content in human hepatocytes. Forced expression of AKAP12 restored alcohol suppressed PKA activation and inhibited lipid accumulation, whereas silencing had the reverse effect. Since AKAP12 sustained PKA activity, we evaluated whether the AKAP12-PKA scaffold was important in lipid homeostasis. Inhibition of AKAP12-PKA interaction by CRISPR deletion of AKAP12’s PKA binding domain in cultured hepatocytes or in mouse models of ALD dramatically suppressed PKA activity, enhanced ACC1 activity demonstrated by reduced inhibitory phosphorylation, increased lipid accumulation and reduced FAO in hepatocytes. Overexpression of AKAP12 in mouse livers sustained PKA activation, diminished basal and alcohol potentiated triglyceride content, and regulated inflammatory signaling altered by alcohol. Mechanistically, we discovered that alcohol enhanced the inhibitory activity of a kinase, serine/threonine-protein kinase 25 (STK25) on PKA that regulated its interaction with AKAP12. In conclusion, the AKAP12-PKA scaffold controls lipogenic signaling, disruption of which favors steatosis during ALD. |
| format | Article |
| id | doaj-art-d42854e520094d92b7dfa2a20031069d |
| institution | OA Journals |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-d42854e520094d92b7dfa2a20031069d2025-08-20T02:11:47ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-04-0110111510.1038/s41392-025-02202-1The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver diseaseChandana Thimme Gowda0Mallikarjuna Siraganahalli Eshwaraiah1Jiaohong Wang2Youngyi Lim3Maria Lauda Tomasi4Nirmala Mavila5Komal Ramani6Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterKarsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterKarsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterKarsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterKarsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterKarsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterKarsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterAbstract Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation (FAO). The goal of this work is to examine how AKAP12’s PKA-anchoring ability regulates outcomes of alcohol-associated steatosis. Crosslinking proteomics identified PKA and its lipogenic substrates as interacting partners of AKAP12. Alcohol exposure diminished AKAP12’s interaction with PKA regulatory subunits and PKA substrates, acetyl CoA carboxylase (ACC1), pyruvate dehydrogenase (PDHA) and adipose triglyceride lipase (ATGL). Alcohol inhibited PKA activity and increased triglyceride content in human hepatocytes. Forced expression of AKAP12 restored alcohol suppressed PKA activation and inhibited lipid accumulation, whereas silencing had the reverse effect. Since AKAP12 sustained PKA activity, we evaluated whether the AKAP12-PKA scaffold was important in lipid homeostasis. Inhibition of AKAP12-PKA interaction by CRISPR deletion of AKAP12’s PKA binding domain in cultured hepatocytes or in mouse models of ALD dramatically suppressed PKA activity, enhanced ACC1 activity demonstrated by reduced inhibitory phosphorylation, increased lipid accumulation and reduced FAO in hepatocytes. Overexpression of AKAP12 in mouse livers sustained PKA activation, diminished basal and alcohol potentiated triglyceride content, and regulated inflammatory signaling altered by alcohol. Mechanistically, we discovered that alcohol enhanced the inhibitory activity of a kinase, serine/threonine-protein kinase 25 (STK25) on PKA that regulated its interaction with AKAP12. In conclusion, the AKAP12-PKA scaffold controls lipogenic signaling, disruption of which favors steatosis during ALD.https://doi.org/10.1038/s41392-025-02202-1 |
| spellingShingle | Chandana Thimme Gowda Mallikarjuna Siraganahalli Eshwaraiah Jiaohong Wang Youngyi Lim Maria Lauda Tomasi Nirmala Mavila Komal Ramani The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease Signal Transduction and Targeted Therapy |
| title | The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease |
| title_full | The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease |
| title_fullStr | The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease |
| title_full_unstemmed | The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease |
| title_short | The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease |
| title_sort | akap12 pka axis regulates lipid homeostasis during alcohol associated liver disease |
| url | https://doi.org/10.1038/s41392-025-02202-1 |
| work_keys_str_mv | AT chandanathimmegowda theakap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT mallikarjunasiraganahallieshwaraiah theakap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT jiaohongwang theakap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT youngyilim theakap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT marialaudatomasi theakap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT nirmalamavila theakap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT komalramani theakap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT chandanathimmegowda akap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT mallikarjunasiraganahallieshwaraiah akap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT jiaohongwang akap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT youngyilim akap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT marialaudatomasi akap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT nirmalamavila akap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease AT komalramani akap12pkaaxisregulateslipidhomeostasisduringalcoholassociatedliverdisease |