Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl<sub>4</sub> and TAA-Induced Liver Fibrosis in Mice
Persistent chronic liver diseases increase the scar formation and extracellular matrix accumulation that further progress to liver fibrosis and cirrhosis. Nevertheless, there is no antifibrotic therapy to date. The ketogenic diet is composed of high fat, moderate to low-protein, and very low carbohy...
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MDPI AG
2021-03-01
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| Online Access: | https://www.mdpi.com/1422-0067/22/6/2934 |
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| author | Yi-Jen Liao Yuan-Hsi Wang Chien-Ying Wu Fang-Yu Hsu Chia-Ying Chien Yi-Chieh Lee |
| author_facet | Yi-Jen Liao Yuan-Hsi Wang Chien-Ying Wu Fang-Yu Hsu Chia-Ying Chien Yi-Chieh Lee |
| author_sort | Yi-Jen Liao |
| collection | DOAJ |
| description | Persistent chronic liver diseases increase the scar formation and extracellular matrix accumulation that further progress to liver fibrosis and cirrhosis. Nevertheless, there is no antifibrotic therapy to date. The ketogenic diet is composed of high fat, moderate to low-protein, and very low carbohydrate content. It is mainly used in epilepsy and Alzheimer’s disease. However, the effects of the ketogenic diet on liver fibrosis remains unknown. Through ketogenic diet consumption, β-hydroxybutyrate (bHB) and acetoacetate (AcAc) are two ketone bodies that are mainly produced in the liver. It is reported that bHB and AcAc treatment decreases cancer cell proliferation and promotes apoptosis. However, the influence of bHB and AcAc in hepatic stellate cell (HSC) activation and liver fibrosis are still unclear. Therefore, this study aimed to investigate the effect of the ketogenic diet and ketone bodies in affecting liver fibrosis progression. Our study revealed that feeding a high-fat ketogenic diet increased cholesterol accumulation in the liver, which further enhanced the carbon tetrachloride (CCl<sub>4</sub>)- and thioacetamide (TAA)-induced liver fibrosis. In addition, more severe liver inflammation and the loss of hepatic antioxidant and detoxification ability were also found in ketogenic diet-fed fibrotic mouse groups. However, the treatment with ketone bodies (bHB and AcAc) did not suppress transforming growth factor-β (TGF-β)-induced HSC activation, platelet-derived growth factor (PDGF)-BB-triggered proliferation, and the severity of CCl<sub>4</sub>-induced liver fibrosis in mice. In conclusion, our study demonstrated that feeding a high-fat ketogenic diet may trigger severe steatohepatitis and thereby promote liver fibrosis progression. Since a different ketogenic diet composition may exert different metabolic effects, more evidence is necessary to clarify the effects of a ketogenic diet on disease treatment. |
| first_indexed | 2024-03-10T13:15:11Z |
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| language | English |
| last_indexed | 2024-03-10T13:15:11Z |
| publishDate | 2021-03-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-24927a3f573d442fb4444a706d8125862023-11-21T10:24:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01226293410.3390/ijms22062934Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl<sub>4</sub> and TAA-Induced Liver Fibrosis in MiceYi-Jen Liao0Yuan-Hsi Wang1Chien-Ying Wu2Fang-Yu Hsu3Chia-Ying Chien4Yi-Chieh Lee5School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanSchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanSchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanSchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanSchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanSchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanPersistent chronic liver diseases increase the scar formation and extracellular matrix accumulation that further progress to liver fibrosis and cirrhosis. Nevertheless, there is no antifibrotic therapy to date. The ketogenic diet is composed of high fat, moderate to low-protein, and very low carbohydrate content. It is mainly used in epilepsy and Alzheimer’s disease. However, the effects of the ketogenic diet on liver fibrosis remains unknown. Through ketogenic diet consumption, β-hydroxybutyrate (bHB) and acetoacetate (AcAc) are two ketone bodies that are mainly produced in the liver. It is reported that bHB and AcAc treatment decreases cancer cell proliferation and promotes apoptosis. However, the influence of bHB and AcAc in hepatic stellate cell (HSC) activation and liver fibrosis are still unclear. Therefore, this study aimed to investigate the effect of the ketogenic diet and ketone bodies in affecting liver fibrosis progression. Our study revealed that feeding a high-fat ketogenic diet increased cholesterol accumulation in the liver, which further enhanced the carbon tetrachloride (CCl<sub>4</sub>)- and thioacetamide (TAA)-induced liver fibrosis. In addition, more severe liver inflammation and the loss of hepatic antioxidant and detoxification ability were also found in ketogenic diet-fed fibrotic mouse groups. However, the treatment with ketone bodies (bHB and AcAc) did not suppress transforming growth factor-β (TGF-β)-induced HSC activation, platelet-derived growth factor (PDGF)-BB-triggered proliferation, and the severity of CCl<sub>4</sub>-induced liver fibrosis in mice. In conclusion, our study demonstrated that feeding a high-fat ketogenic diet may trigger severe steatohepatitis and thereby promote liver fibrosis progression. Since a different ketogenic diet composition may exert different metabolic effects, more evidence is necessary to clarify the effects of a ketogenic diet on disease treatment.https://www.mdpi.com/1422-0067/22/6/2934high-fat ketogenic dietliver fibrosisβ-hydroxybutyrateacetoacetatehepatic stellate cells |
| spellingShingle | Yi-Jen Liao Yuan-Hsi Wang Chien-Ying Wu Fang-Yu Hsu Chia-Ying Chien Yi-Chieh Lee Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl<sub>4</sub> and TAA-Induced Liver Fibrosis in Mice International Journal of Molecular Sciences high-fat ketogenic diet liver fibrosis β-hydroxybutyrate acetoacetate hepatic stellate cells |
| title | Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl<sub>4</sub> and TAA-Induced Liver Fibrosis in Mice |
| title_full | Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl<sub>4</sub> and TAA-Induced Liver Fibrosis in Mice |
| title_fullStr | Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl<sub>4</sub> and TAA-Induced Liver Fibrosis in Mice |
| title_full_unstemmed | Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl<sub>4</sub> and TAA-Induced Liver Fibrosis in Mice |
| title_short | Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl<sub>4</sub> and TAA-Induced Liver Fibrosis in Mice |
| title_sort | ketogenic diet enhances the cholesterol accumulation in liver and augments the severity of ccl sub 4 sub and taa induced liver fibrosis in mice |
| topic | high-fat ketogenic diet liver fibrosis β-hydroxybutyrate acetoacetate hepatic stellate cells |
| url | https://www.mdpi.com/1422-0067/22/6/2934 |
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