Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells
<b>Background:</b> Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in...
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2025-02-01
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| author | Ya Zhou Feixia Wang Mengru Hu Siwei Xia Yang Li Shizhong Zheng Feng Zhang |
| author_facet | Ya Zhou Feixia Wang Mengru Hu Siwei Xia Yang Li Shizhong Zheng Feng Zhang |
| author_sort | Ya Zhou |
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| description | <b>Background:</b> Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the mechanisms linking ketone metabolism to fibrosis progression remain unclear. <b>Objectives:</b> This study aimed to investigate the role of AcAc in modulating HSCs activation and its potential mechanisms in HF. <b>Methods:</b> We examined the effects of AcAc on HSCs activation by Western blot analysis and RT-PCR both in vivo and in vitro. The impact of AcAc on lipid droplet accumulation in HSCs was assessed using total cholesterol (TC), triglyceride (TG), and Retinol (RET) kits, along with Nile Red and Oil Red O staining. RT-PCR screening was performed to analyze the expression of genes involved in lipid droplet formation and lipid metabolism. <b>Results:</b> Our findings show that AcAc inhibited HSCs activation by restoring LD levels. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) was identified as a key regulator through gene screening. AcAc primarily regulated PPARγ expression, and knocking down PPARγ significantly aggravated HF progression. <b>Conclusions:</b> The ability of AcAc to restore LD levels and regulate PPARγ suggests that it may represent a promising therapeutic strategy for HF by inhibiting HSCs activation. |
| format | Article |
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| issn | 1424-8247 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-008b381fd5a04f81be5992c7f29191dd2025-08-20T02:03:27ZengMDPI AGPharmaceuticals1424-82472025-02-0118221910.3390/ph18020219Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate CellsYa Zhou0Feixia Wang1Mengru Hu2Siwei Xia3Yang Li4Shizhong Zheng5Feng Zhang6Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China<b>Background:</b> Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the mechanisms linking ketone metabolism to fibrosis progression remain unclear. <b>Objectives:</b> This study aimed to investigate the role of AcAc in modulating HSCs activation and its potential mechanisms in HF. <b>Methods:</b> We examined the effects of AcAc on HSCs activation by Western blot analysis and RT-PCR both in vivo and in vitro. The impact of AcAc on lipid droplet accumulation in HSCs was assessed using total cholesterol (TC), triglyceride (TG), and Retinol (RET) kits, along with Nile Red and Oil Red O staining. RT-PCR screening was performed to analyze the expression of genes involved in lipid droplet formation and lipid metabolism. <b>Results:</b> Our findings show that AcAc inhibited HSCs activation by restoring LD levels. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) was identified as a key regulator through gene screening. AcAc primarily regulated PPARγ expression, and knocking down PPARγ significantly aggravated HF progression. <b>Conclusions:</b> The ability of AcAc to restore LD levels and regulate PPARγ suggests that it may represent a promising therapeutic strategy for HF by inhibiting HSCs activation.https://www.mdpi.com/1424-8247/18/2/219hepatic fibrosisacetoacetatePPARγlipid droplets |
| spellingShingle | Ya Zhou Feixia Wang Mengru Hu Siwei Xia Yang Li Shizhong Zheng Feng Zhang Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells Pharmaceuticals hepatic fibrosis acetoacetate PPARγ lipid droplets |
| title | Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells |
| title_full | Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells |
| title_fullStr | Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells |
| title_full_unstemmed | Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells |
| title_short | Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells |
| title_sort | acetoacetate ameliorates hepatic fibrosis by targeting peroxisome proliferator activated receptor gamma to restore lipid droplets in activated hepatic stellate cells |
| topic | hepatic fibrosis acetoacetate PPARγ lipid droplets |
| url | https://www.mdpi.com/1424-8247/18/2/219 |
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