Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease
Abstract Background Non-alcoholic steatohepatitis (NASH) progression is strongly associated with deteriorating hepatic function, primarily driven by free cholesterol (FC) accumulation-induced lipotoxicity. Emerging evidence highlights the regulatory role of mammalian Ste20-like kinase 1 (MST1) in mo...
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BMC
2025-04-01
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| Series: | European Journal of Medical Research |
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| Online Access: | https://doi.org/10.1186/s40001-025-02557-9 |
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| author | Lijuan Wang Chenglei Zhang Jie Ma Jiarui Li Yuanyuan Wu Yanru Ren Jianning Li Yan Li Yi Yang |
| author_facet | Lijuan Wang Chenglei Zhang Jie Ma Jiarui Li Yuanyuan Wu Yanru Ren Jianning Li Yan Li Yi Yang |
| author_sort | Lijuan Wang |
| collection | DOAJ |
| description | Abstract Background Non-alcoholic steatohepatitis (NASH) progression is strongly associated with deteriorating hepatic function, primarily driven by free cholesterol (FC) accumulation-induced lipotoxicity. Emerging evidence highlights the regulatory role of mammalian Ste20-like kinase 1 (MST1) in modulating intrahepatic lipid homeostasis, suggesting its therapeutic potential for non-alcoholic fatty liver disease (NAFLD) management. This investigation seeks to elucidate the pathophysiological mechanisms through which MST1 modulates NASH progression. Methods The experimental design employed two murine genetic models—wild-type (WT) controls and MST1-knockout (MST1-KO) specimens—subjected to a nutritionally modified Western diet (WD) enriched with saturated fats, simple carbohydrates, and dietary cholesterol to induce non-alcoholic steatohepatitis (NASH) pathogenesis. Lentiviral transduction techniques facilitated targeted MST1 overexpression in WT animals maintained on this dietary regimen. Parallel in vitro investigations utilized HepG2 hepatocyte cultures exposed to free fatty acid (FFA) cocktails comprising palmitic and oleic acids, coupled with CRISPR-mediated MST1 suppression and complementary gain-of-function manipulations to delineate molecular mechanisms. Results NASH triggers hepatic sterol biosynthesis activation, resulting in pathological FC overload concurrent with MST1 transcriptional suppression. Genetic ablation of MST1 amplifies intrahepatic FC retention and potentiates histopathological inflammation, while MST1 reconstitution mitigates steatotic FC deposition and attenuates inflammatory cascades. Mechanistic profiling revealed MST1-mediated AMPKα phosphorylation at Thr172, which suppresses cholesterogenic enzyme expression via sterol regulatory element-binding transcription factor 2 (SREBP2) axis modulation. This phosphorylation cascade demonstrates dose-dependent inhibition of HMGCR activity, resolving FC-induced hepatotoxicity. Crucially, MST1 orchestrates AMPK/SREBP2 crosstalk to maintain sterol homeostasis, with knockout models exhibiting 67% elevated SREBP2 nuclear translocation compared to controls. Conclusions The regulatory axis involving MST1-mediated AMPK phosphorylation emerges as a promising therapeutic modality for modulating hepatic sterol metabolism. It demonstrates significant potential in arresting the progression of inflammatory cascades and extracellular matrix remodeling characteristic of NASH pathogenesis. Mechanistic studies confirm that this phosphorylation cascade effectively suppresses de novo lipogenesis while enhancing cholesterol efflux capacity, thereby establishing a dual-target strategy against both metabolic dysfunction and fibrotic transformation in preclinical models. |
| format | Article |
| id | doaj-art-5c7e3bbd45594807814a9dcd48e19654 |
| institution | OA Journals |
| issn | 2047-783X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | European Journal of Medical Research |
| spelling | doaj-art-5c7e3bbd45594807814a9dcd48e196542025-08-20T02:27:51ZengBMCEuropean Journal of Medical Research2047-783X2025-04-0130112010.1186/s40001-025-02557-9Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver diseaseLijuan Wang0Chenglei Zhang1Jie Ma2Jiarui Li3Yuanyuan Wu4Yanru Ren5Jianning Li6Yan Li7Yi Yang8School of Basic Medical Sciences, Ningxia Medical UniversityMedical Laboratory, General Hospital of Ningxia Medical UniversitySchool of Basic Medical Sciences, Ningxia Medical UniversitySchool of Basic Medical Sciences, Ningxia Medical UniversityDepartment of Oncology, Cancer Hospital, General Hospital of Ningxia Medical UniversityDepartment of Endocrinology, General Hospital of Ningxia Medical UniversitySchool of Basic Medical Sciences, Ningxia Medical UniversitySchool of Basic Medical Sciences, Ningxia Medical UniversitySchool of Basic Medical Sciences, Ningxia Medical UniversityAbstract Background Non-alcoholic steatohepatitis (NASH) progression is strongly associated with deteriorating hepatic function, primarily driven by free cholesterol (FC) accumulation-induced lipotoxicity. Emerging evidence highlights the regulatory role of mammalian Ste20-like kinase 1 (MST1) in modulating intrahepatic lipid homeostasis, suggesting its therapeutic potential for non-alcoholic fatty liver disease (NAFLD) management. This investigation seeks to elucidate the pathophysiological mechanisms through which MST1 modulates NASH progression. Methods The experimental design employed two murine genetic models—wild-type (WT) controls and MST1-knockout (MST1-KO) specimens—subjected to a nutritionally modified Western diet (WD) enriched with saturated fats, simple carbohydrates, and dietary cholesterol to induce non-alcoholic steatohepatitis (NASH) pathogenesis. Lentiviral transduction techniques facilitated targeted MST1 overexpression in WT animals maintained on this dietary regimen. Parallel in vitro investigations utilized HepG2 hepatocyte cultures exposed to free fatty acid (FFA) cocktails comprising palmitic and oleic acids, coupled with CRISPR-mediated MST1 suppression and complementary gain-of-function manipulations to delineate molecular mechanisms. Results NASH triggers hepatic sterol biosynthesis activation, resulting in pathological FC overload concurrent with MST1 transcriptional suppression. Genetic ablation of MST1 amplifies intrahepatic FC retention and potentiates histopathological inflammation, while MST1 reconstitution mitigates steatotic FC deposition and attenuates inflammatory cascades. Mechanistic profiling revealed MST1-mediated AMPKα phosphorylation at Thr172, which suppresses cholesterogenic enzyme expression via sterol regulatory element-binding transcription factor 2 (SREBP2) axis modulation. This phosphorylation cascade demonstrates dose-dependent inhibition of HMGCR activity, resolving FC-induced hepatotoxicity. Crucially, MST1 orchestrates AMPK/SREBP2 crosstalk to maintain sterol homeostasis, with knockout models exhibiting 67% elevated SREBP2 nuclear translocation compared to controls. Conclusions The regulatory axis involving MST1-mediated AMPK phosphorylation emerges as a promising therapeutic modality for modulating hepatic sterol metabolism. It demonstrates significant potential in arresting the progression of inflammatory cascades and extracellular matrix remodeling characteristic of NASH pathogenesis. Mechanistic studies confirm that this phosphorylation cascade effectively suppresses de novo lipogenesis while enhancing cholesterol efflux capacity, thereby establishing a dual-target strategy against both metabolic dysfunction and fibrotic transformation in preclinical models.https://doi.org/10.1186/s40001-025-02557-9Mammalian sterile 20-like kinase 1AMP-activated protein kinaseCholesterol synthesisHepatic free cholesterolNon-alcoholic steatohepatitis |
| spellingShingle | Lijuan Wang Chenglei Zhang Jie Ma Jiarui Li Yuanyuan Wu Yanru Ren Jianning Li Yan Li Yi Yang Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease European Journal of Medical Research Mammalian sterile 20-like kinase 1 AMP-activated protein kinase Cholesterol synthesis Hepatic free cholesterol Non-alcoholic steatohepatitis |
| title | Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease |
| title_full | Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease |
| title_fullStr | Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease |
| title_full_unstemmed | Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease |
| title_short | Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease |
| title_sort | mammalian ste20 like kinase 1 regulates ampk to mitigate the progression of non alcoholic fatty liver disease |
| topic | Mammalian sterile 20-like kinase 1 AMP-activated protein kinase Cholesterol synthesis Hepatic free cholesterol Non-alcoholic steatohepatitis |
| url | https://doi.org/10.1186/s40001-025-02557-9 |
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