Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl 4 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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| 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
)- 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
-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. |
| format | Article |
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)- 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
-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.</description><identifier>EISSN: 1422-0067</identifier><identifier>PMID: 33805788</identifier><language>eng</language><publisher>Switzerland</publisher><subject>3-Hydroxybutyric Acid - biosynthesis ; 3-Hydroxybutyric Acid - pharmacology ; Acetoacetates - metabolism ; Acetoacetates - pharmacology ; Actins - genetics ; Actins - metabolism ; Animals ; Becaplermin - pharmacology ; Carbon Tetrachloride - administration & dosage ; Catalase - genetics ; Catalase - metabolism ; Cell Proliferation - drug effects ; Cholesterol - biosynthesis ; Cholesterol - blood ; Collagen Type I - genetics ; Collagen Type I - metabolism ; Cytochrome P-450 CYP1A2 - genetics ; Cytochrome P-450 CYP1A2 - metabolism ; Desmin - genetics ; Desmin - metabolism ; Diet, Ketogenic - adverse effects ; Disease Progression ; Gene Expression Regulation - drug effects ; Hepatic Stellate Cells - cytology ; Hepatic Stellate Cells - drug effects ; Hepatic Stellate Cells - metabolism ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Liver Cirrhosis - chemically induced ; Liver Cirrhosis - genetics ; Liver Cirrhosis - metabolism ; Liver Cirrhosis - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Primary Cell Culture ; Severity of Illness Index ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism ; Superoxide Dismutase-1 - genetics ; Superoxide Dismutase-1 - metabolism ; Thioacetamide - administration & dosage ; Transforming Growth Factor beta - biosynthesis ; Transforming Growth Factor beta - pharmacology</subject><ispartof>International journal of molecular sciences, 2021-03, Vol.22 (6)</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-9836-1503</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33805788$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liao, Yi-Jen</creatorcontrib><creatorcontrib>Wang, Yuan-Hsi</creatorcontrib><creatorcontrib>Wu, Chien-Ying</creatorcontrib><creatorcontrib>Hsu, Fang-Yu</creatorcontrib><creatorcontrib>Chien, Chia-Ying</creatorcontrib><creatorcontrib>Lee, Yi-Chieh</creatorcontrib><title>Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl 4 and TAA-Induced Liver Fibrosis in Mice</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><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
)- 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
-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.</description><subject>3-Hydroxybutyric Acid - biosynthesis</subject><subject>3-Hydroxybutyric Acid - pharmacology</subject><subject>Acetoacetates - metabolism</subject><subject>Acetoacetates - pharmacology</subject><subject>Actins - genetics</subject><subject>Actins - metabolism</subject><subject>Animals</subject><subject>Becaplermin - pharmacology</subject><subject>Carbon Tetrachloride - administration & dosage</subject><subject>Catalase - genetics</subject><subject>Catalase - metabolism</subject><subject>Cell Proliferation - drug effects</subject><subject>Cholesterol - biosynthesis</subject><subject>Cholesterol - blood</subject><subject>Collagen Type I - genetics</subject><subject>Collagen Type I - metabolism</subject><subject>Cytochrome P-450 CYP1A2 - genetics</subject><subject>Cytochrome P-450 CYP1A2 - metabolism</subject><subject>Desmin - genetics</subject><subject>Desmin - metabolism</subject><subject>Diet, Ketogenic - adverse effects</subject><subject>Disease Progression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Hepatic Stellate Cells - cytology</subject><subject>Hepatic Stellate Cells - drug effects</subject><subject>Hepatic Stellate Cells - metabolism</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver Cirrhosis - chemically induced</subject><subject>Liver Cirrhosis - genetics</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Liver Cirrhosis - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Primary Cell Culture</subject><subject>Severity of Illness Index</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase - metabolism</subject><subject>Superoxide Dismutase-1 - genetics</subject><subject>Superoxide Dismutase-1 - metabolism</subject><subject>Thioacetamide - administration & dosage</subject><subject>Transforming Growth Factor beta - biosynthesis</subject><subject>Transforming Growth Factor beta - pharmacology</subject><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjs1qwkAUhYeCmNj2FeS-QGBM1MRlSA0VdaV7GSdXc8tkRuZH8Al87bb-rF0dOHzf4byxeDRO04TzaR6xgXM_nKdZOpn1WZRlBZ_kRRGz6xK9OaImCV-EHua6FVqiA98iVK1R6Dxao6CUMnRBCU9GA2lY0RktCN1AGY4dan9XNvhXk7-AOUBVKRjfkG1ZJgvdBInNQ6xpb40j9z-1JokfrHcQyuHnI9_ZsJ5vq-_kFPYdNruTpU7Yy-75PHsJ_AJg8k6v</recordid><startdate>20210313</startdate><enddate>20210313</enddate><creator>Liao, Yi-Jen</creator><creator>Wang, Yuan-Hsi</creator><creator>Wu, Chien-Ying</creator><creator>Hsu, Fang-Yu</creator><creator>Chien, Chia-Ying</creator><creator>Lee, Yi-Chieh</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><orcidid>https://orcid.org/0000-0002-9836-1503</orcidid></search><sort><creationdate>20210313</creationdate><title>Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl 4 and TAA-Induced Liver Fibrosis in Mice</title><author>Liao, Yi-Jen ; Wang, Yuan-Hsi ; Wu, Chien-Ying ; Hsu, Fang-Yu ; Chien, Chia-Ying ; Lee, Yi-Chieh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_338057883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>3-Hydroxybutyric Acid - biosynthesis</topic><topic>3-Hydroxybutyric Acid - pharmacology</topic><topic>Acetoacetates - metabolism</topic><topic>Acetoacetates - pharmacology</topic><topic>Actins - genetics</topic><topic>Actins - metabolism</topic><topic>Animals</topic><topic>Becaplermin - pharmacology</topic><topic>Carbon Tetrachloride - administration & dosage</topic><topic>Catalase - genetics</topic><topic>Catalase - metabolism</topic><topic>Cell Proliferation - drug effects</topic><topic>Cholesterol - biosynthesis</topic><topic>Cholesterol - blood</topic><topic>Collagen Type I - genetics</topic><topic>Collagen Type I - metabolism</topic><topic>Cytochrome P-450 CYP1A2 - genetics</topic><topic>Cytochrome P-450 CYP1A2 - metabolism</topic><topic>Desmin - genetics</topic><topic>Desmin - metabolism</topic><topic>Diet, Ketogenic - adverse effects</topic><topic>Disease Progression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Hepatic Stellate Cells - cytology</topic><topic>Hepatic Stellate Cells - drug effects</topic><topic>Hepatic Stellate Cells - metabolism</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Liver Cirrhosis - chemically induced</topic><topic>Liver Cirrhosis - genetics</topic><topic>Liver Cirrhosis - metabolism</topic><topic>Liver Cirrhosis - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Primary Cell Culture</topic><topic>Severity of Illness Index</topic><topic>Superoxide Dismutase - genetics</topic><topic>Superoxide Dismutase - metabolism</topic><topic>Superoxide Dismutase-1 - genetics</topic><topic>Superoxide Dismutase-1 - metabolism</topic><topic>Thioacetamide - administration & dosage</topic><topic>Transforming Growth Factor beta - biosynthesis</topic><topic>Transforming Growth Factor beta - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liao, Yi-Jen</creatorcontrib><creatorcontrib>Wang, Yuan-Hsi</creatorcontrib><creatorcontrib>Wu, Chien-Ying</creatorcontrib><creatorcontrib>Hsu, Fang-Yu</creatorcontrib><creatorcontrib>Chien, Chia-Ying</creatorcontrib><creatorcontrib>Lee, Yi-Chieh</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liao, Yi-Jen</au><au>Wang, Yuan-Hsi</au><au>Wu, Chien-Ying</au><au>Hsu, Fang-Yu</au><au>Chien, Chia-Ying</au><au>Lee, Yi-Chieh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl 4 and TAA-Induced Liver Fibrosis in Mice</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2021-03-13</date><risdate>2021</risdate><volume>22</volume><issue>6</issue><eissn>1422-0067</eissn><abstract>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
)- 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
-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.</abstract><cop>Switzerland</cop><pmid>33805788</pmid><orcidid>https://orcid.org/0000-0002-9836-1503</orcidid></addata></record> |
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| ispartof | International journal of molecular sciences, 2021-03, Vol.22 (6) |
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| source | MEDLINE; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | 3-Hydroxybutyric Acid - biosynthesis 3-Hydroxybutyric Acid - pharmacology Acetoacetates - metabolism Acetoacetates - pharmacology Actins - genetics Actins - metabolism Animals Becaplermin - pharmacology Carbon Tetrachloride - administration & dosage Catalase - genetics Catalase - metabolism Cell Proliferation - drug effects Cholesterol - biosynthesis Cholesterol - blood Collagen Type I - genetics Collagen Type I - metabolism Cytochrome P-450 CYP1A2 - genetics Cytochrome P-450 CYP1A2 - metabolism Desmin - genetics Desmin - metabolism Diet, Ketogenic - adverse effects Disease Progression Gene Expression Regulation - drug effects Hepatic Stellate Cells - cytology Hepatic Stellate Cells - drug effects Hepatic Stellate Cells - metabolism Liver - drug effects Liver - metabolism Liver - pathology Liver Cirrhosis - chemically induced Liver Cirrhosis - genetics Liver Cirrhosis - metabolism Liver Cirrhosis - pathology Male Mice Mice, Inbred C57BL Primary Cell Culture Severity of Illness Index Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Superoxide Dismutase-1 - genetics Superoxide Dismutase-1 - metabolism Thioacetamide - administration & dosage Transforming Growth Factor beta - biosynthesis Transforming Growth Factor beta - pharmacology |
| title | Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl 4 and TAA-Induced Liver Fibrosis in Mice |
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