Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease
Abstract RelA, also known as nuclear factor kappa B p65, plays a crucial role in the pathogenesis of various liver diseases. However, the specific role of RelA in hepatocytes during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is not well understood. This study...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-02-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02312-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823863244967641088 |
|---|---|
| author | Yihuai He Jinlian Jiang Lili Ou Yunfen Chen Aikedaimu Abudukeremu Guimei Chen Weiwei Zhong Zhigang Jiang Nuerbiye Nuermaimaiti Yaqun Guan |
| author_facet | Yihuai He Jinlian Jiang Lili Ou Yunfen Chen Aikedaimu Abudukeremu Guimei Chen Weiwei Zhong Zhigang Jiang Nuerbiye Nuermaimaiti Yaqun Guan |
| author_sort | Yihuai He |
| collection | DOAJ |
| description | Abstract RelA, also known as nuclear factor kappa B p65, plays a crucial role in the pathogenesis of various liver diseases. However, the specific role of RelA in hepatocytes during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is not well understood. This study explored the relationship between impaired RelA signaling and lipid metabolism disorders in hepatocytes, and how they synergistically contribute to the advancement of MASLD. We assessed the changes, regulatory relationships, and impacts of RelA signaling and lipid metabolism remodeling on disease progression both in vitro and in vivo. During MASLD, there was a decrease in the expression of RelA and hepatocyte nuclear factor 1 alpha (HNF1α), with both factors showing mutual enhancement of each other’s expression under normal conditions. This synergistic effect was absent during hepatocyte steatosis. RelA or HNF1α depletion in hepatocytes intensified MASLD symptoms, whereas overexpression of RELA or treatment with necrostatin-1 (a necroptosis inhibitor) or Z-VAD (a caspase inhibitor) significantly mitigated these effects. Mechanistically, during hepatic steatosis, altered lipid profiles exhibited lipotoxicity, inducing hepatocyte apoptosis and necroptosis, whereas endoplasmic reticulum (ER) stress triggered lipid remodeling processes similar to those observed in MASLD. RelA signaling upregulated the expression of activating transcription factor 4 and glucose-regulated protein 78, thereby alleviating ER stress. Impaired RelA signaling remodeled the ER stress response and lipid metabolism, and enhanced lipid accumulation and lipid toxicity. In conclusion, impaired RelA signaling and disrupted lipid metabolism form a detrimental feedback loop in hepatocytes that promotes MASLD progression. Lipid accumulation suppresses RelA signaling, remodeling the ER stress response and exacerbating lipid metabolism disorder, ultimately leading to hepatocyte apoptosis and necroptosis. |
| format | Article |
| id | doaj-art-0d5afc95cf1742a4b5ea9163337cc9e8 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-0d5afc95cf1742a4b5ea9163337cc9e82025-02-09T12:12:32ZengNature Publishing GroupCell Death Discovery2058-77162025-02-0111112110.1038/s41420-025-02312-3Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver diseaseYihuai He0Jinlian Jiang1Lili Ou2Yunfen Chen3Aikedaimu Abudukeremu4Guimei Chen5Weiwei Zhong6Zhigang Jiang7Nuerbiye Nuermaimaiti8Yaqun Guan9State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical UniversityDepartment of Infectious Diseases, Affiliated Hospital of Zunyi Medical UniversityDepartment of Infectious Diseases, Affiliated Hospital of Zunyi Medical UniversityDepartment of Infectious Diseases, Affiliated Hospital of Zunyi Medical UniversityState Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical UniversityDepartment of Infectious Diseases, Affiliated Hospital of Zunyi Medical UniversityDepartment of Infectious Diseases, Jingmen Central HospitalSchool of Public Health, Zunyi Medical UniversityState Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical UniversityState Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical UniversityAbstract RelA, also known as nuclear factor kappa B p65, plays a crucial role in the pathogenesis of various liver diseases. However, the specific role of RelA in hepatocytes during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is not well understood. This study explored the relationship between impaired RelA signaling and lipid metabolism disorders in hepatocytes, and how they synergistically contribute to the advancement of MASLD. We assessed the changes, regulatory relationships, and impacts of RelA signaling and lipid metabolism remodeling on disease progression both in vitro and in vivo. During MASLD, there was a decrease in the expression of RelA and hepatocyte nuclear factor 1 alpha (HNF1α), with both factors showing mutual enhancement of each other’s expression under normal conditions. This synergistic effect was absent during hepatocyte steatosis. RelA or HNF1α depletion in hepatocytes intensified MASLD symptoms, whereas overexpression of RELA or treatment with necrostatin-1 (a necroptosis inhibitor) or Z-VAD (a caspase inhibitor) significantly mitigated these effects. Mechanistically, during hepatic steatosis, altered lipid profiles exhibited lipotoxicity, inducing hepatocyte apoptosis and necroptosis, whereas endoplasmic reticulum (ER) stress triggered lipid remodeling processes similar to those observed in MASLD. RelA signaling upregulated the expression of activating transcription factor 4 and glucose-regulated protein 78, thereby alleviating ER stress. Impaired RelA signaling remodeled the ER stress response and lipid metabolism, and enhanced lipid accumulation and lipid toxicity. In conclusion, impaired RelA signaling and disrupted lipid metabolism form a detrimental feedback loop in hepatocytes that promotes MASLD progression. Lipid accumulation suppresses RelA signaling, remodeling the ER stress response and exacerbating lipid metabolism disorder, ultimately leading to hepatocyte apoptosis and necroptosis.https://doi.org/10.1038/s41420-025-02312-3 |
| spellingShingle | Yihuai He Jinlian Jiang Lili Ou Yunfen Chen Aikedaimu Abudukeremu Guimei Chen Weiwei Zhong Zhigang Jiang Nuerbiye Nuermaimaiti Yaqun Guan Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease Cell Death Discovery |
| title | Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease |
| title_full | Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease |
| title_fullStr | Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease |
| title_full_unstemmed | Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease |
| title_short | Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease |
| title_sort | impaired rela signaling and lipid metabolism dysregulation in hepatocytes driving forces in the progression of metabolic dysfunction associated steatotic liver disease |
| url | https://doi.org/10.1038/s41420-025-02312-3 |
| work_keys_str_mv | AT yihuaihe impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT jinlianjiang impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT liliou impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT yunfenchen impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT aikedaimuabudukeremu impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT guimeichen impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT weiweizhong impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT zhigangjiang impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT nuerbiyenuermaimaiti impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease AT yaqunguan impairedrelasignalingandlipidmetabolismdysregulationinhepatocytesdrivingforcesintheprogressionofmetabolicdysfunctionassociatedsteatoticliverdisease |