Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction‐associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways
Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprote...
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| Veröffentlicht in: | International journal of experimental pathology 2024-12, Vol.105 (6), p.219-234 |
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| creator | Farrash, Wesam F. Idris, Shakir Elzubier, Mohamed E. Khidir, Elshiekh B. A. Aslam, Akhmed Mujalli, Abdulrahman Almaimani, Riyad A. Obaid, Ahmad A. El‐Readi, Mahmoud Z. Alobaidy, Mohammad A. Salaka, Afnan Shakoori, Afnan M. Saleh, Alaa M. Minshawi, Faisal Samkari, Jamil A. Alshehre, Sallwa M. Refaat, Bassem |
| description | Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose‐transporting and lipid‐regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co‐therapy against diabetes‐induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti‐inflammatory, anti‐oxidative, and anti‐fibrotic pathways. |
| doi_str_mv | 10.1111/iep.12519 |
| format | Article |
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A. ; Aslam, Akhmed ; Mujalli, Abdulrahman ; Almaimani, Riyad A. ; Obaid, Ahmad A. ; El‐Readi, Mahmoud Z. ; Alobaidy, Mohammad A. ; Salaka, Afnan ; Shakoori, Afnan M. ; Saleh, Alaa M. ; Minshawi, Faisal ; Samkari, Jamil A. ; Alshehre, Sallwa M. ; Refaat, Bassem</creator><creatorcontrib>Farrash, Wesam F. ; Idris, Shakir ; Elzubier, Mohamed E. ; Khidir, Elshiekh B. A. ; Aslam, Akhmed ; Mujalli, Abdulrahman ; Almaimani, Riyad A. ; Obaid, Ahmad A. ; El‐Readi, Mahmoud Z. ; Alobaidy, Mohammad A. ; Salaka, Afnan ; Shakoori, Afnan M. ; Saleh, Alaa M. ; Minshawi, Faisal ; Samkari, Jamil A. ; Alshehre, Sallwa M. ; Refaat, Bassem</creatorcontrib><description>Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose‐transporting and lipid‐regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co‐therapy against diabetes‐induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti‐inflammatory, anti‐oxidative, and anti‐fibrotic pathways.</description><identifier>ISSN: 0959-9673</identifier><identifier>ISSN: 1365-2613</identifier><identifier>EISSN: 1365-2613</identifier><identifier>DOI: 10.1111/iep.12519</identifier><identifier>PMID: 39397269</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Animals ; Apoptosis ; Benzhydryl Compounds - pharmacology ; Caspase ; cholecalciferol ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Type 2 - complications ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Diet ; Diet, High-Fat - adverse effects ; Drug Therapy, Combination ; Dyslipidemia ; Fatty liver ; Fibrosis ; Fructose ; Glucose ; Glucose transporter ; Glucosides - pharmacology ; Glucosides - therapeutic use ; High fat diet ; Hydrogen peroxide ; Hyperglycemia ; Inflammation ; Inflammation - drug therapy ; Inflammation - metabolism ; Lipids ; Lipogenesis ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Liver diseases ; liver fibrosis ; Male ; Metabolic disorders ; Mice ; Modulation ; Non-alcoholic Fatty Liver Disease - drug therapy ; Non-alcoholic Fatty Liver Disease - metabolism ; non‐alcoholic fatty liver disease ; Oxidative stress ; Oxidative Stress - drug effects ; PI3K/mTOR pathway ; PTEN protein ; SGLT2 inhibitor ; Signal Transduction - drug effects ; Sodium-glucose cotransporter ; Sodium-Glucose Transporter 2 Inhibitors - pharmacology ; Sterol regulatory element-binding protein ; Superoxide dismutase ; TOR protein ; Vitamin D ; Vitamin D - analogs & derivatives ; Vitamin D - pharmacology ; Vitamin D3</subject><ispartof>International journal of experimental pathology, 2024-12, Vol.105 (6), p.219-234</ispartof><rights>2024 Company of the International Journal of Experimental Pathology (CIJEP).</rights><rights>International Journal of Experimental Pathology © 2024 International Journal of Experimental Pathology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2789-ba9676a21175d0d1ffb73b2420f078b5f3176e612d05d577107316d6ac0f15183</cites><orcidid>0000-0003-4267-1016 ; 0000-0002-6911-9179</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fiep.12519$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fiep.12519$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39397269$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Farrash, Wesam F.</creatorcontrib><creatorcontrib>Idris, Shakir</creatorcontrib><creatorcontrib>Elzubier, Mohamed E.</creatorcontrib><creatorcontrib>Khidir, Elshiekh B. A.</creatorcontrib><creatorcontrib>Aslam, Akhmed</creatorcontrib><creatorcontrib>Mujalli, Abdulrahman</creatorcontrib><creatorcontrib>Almaimani, Riyad A.</creatorcontrib><creatorcontrib>Obaid, Ahmad A.</creatorcontrib><creatorcontrib>El‐Readi, Mahmoud Z.</creatorcontrib><creatorcontrib>Alobaidy, Mohammad A.</creatorcontrib><creatorcontrib>Salaka, Afnan</creatorcontrib><creatorcontrib>Shakoori, Afnan M.</creatorcontrib><creatorcontrib>Saleh, Alaa M.</creatorcontrib><creatorcontrib>Minshawi, Faisal</creatorcontrib><creatorcontrib>Samkari, Jamil A.</creatorcontrib><creatorcontrib>Alshehre, Sallwa M.</creatorcontrib><creatorcontrib>Refaat, Bassem</creatorcontrib><title>Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction‐associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways</title><title>International journal of experimental pathology</title><addtitle>Int J Exp Pathol</addtitle><description>Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose‐transporting and lipid‐regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co‐therapy against diabetes‐induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti‐inflammatory, anti‐oxidative, and anti‐fibrotic pathways.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Benzhydryl Compounds - pharmacology</subject><subject>Caspase</subject><subject>cholecalciferol</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes Mellitus, Type 2 - complications</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diet</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Drug Therapy, Combination</subject><subject>Dyslipidemia</subject><subject>Fatty liver</subject><subject>Fibrosis</subject><subject>Fructose</subject><subject>Glucose</subject><subject>Glucose transporter</subject><subject>Glucosides - pharmacology</subject><subject>Glucosides - therapeutic use</subject><subject>High fat diet</subject><subject>Hydrogen peroxide</subject><subject>Hyperglycemia</subject><subject>Inflammation</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - metabolism</subject><subject>Lipids</subject><subject>Lipogenesis</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver diseases</subject><subject>liver fibrosis</subject><subject>Male</subject><subject>Metabolic disorders</subject><subject>Mice</subject><subject>Modulation</subject><subject>Non-alcoholic Fatty Liver Disease - drug therapy</subject><subject>Non-alcoholic Fatty Liver Disease - metabolism</subject><subject>non‐alcoholic fatty liver disease</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>PI3K/mTOR pathway</subject><subject>PTEN protein</subject><subject>SGLT2 inhibitor</subject><subject>Signal Transduction - drug effects</subject><subject>Sodium-glucose cotransporter</subject><subject>Sodium-Glucose Transporter 2 Inhibitors - pharmacology</subject><subject>Sterol regulatory element-binding protein</subject><subject>Superoxide dismutase</subject><subject>TOR protein</subject><subject>Vitamin D</subject><subject>Vitamin D - analogs & derivatives</subject><subject>Vitamin D - pharmacology</subject><subject>Vitamin D3</subject><issn>0959-9673</issn><issn>1365-2613</issn><issn>1365-2613</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFu1DAURS0EokNhwQ8gS2xA6rR-8cQeL1EZoFIlWMA6eontjis7DrHTElZ8Ap-I-BI8M6ULJLyxF8fnXb1LyHNgp1DOmTPDKVQ1qAdkAVzUy0oAf0gWTNVqqYTkR-RJSteMAa9APiZHXHElK6EW5Nem32LfGU23ZsAchzFm02V3Y6ixtrwSjZaaMOCVd9bH766n2Gt64zKG8n5L9YSe5q0ZcZgpXqHrU6bBZGyjdx3Vc7JTX4yx__3jJ6YUO4e5zEvZlHn7qS67RIssuM7QdqZtjGmHhKgnj7uvuxD3zhMavzmN-5Apjyalk30m11uPIRTrONOi3d7inJ6SRxZ9Ms_u7mPy5d3m8_mH5eXH9xfnby6XXSXXatli2ZPACkDWmmmwtpW8rVYVs0yu29pykMIIqDSrdS0lMMlBaIEds1DDmh-TVwdv2eDXyaTcBJc64z32Jk6p4QCCcwFqVdCX_6DXcRr7kq5QnK1UzVayUK8PVDfGlEZjm2F0Ace5Adbsam9K7c2-9sK-uDNObTD6nvzbcwHODsCt82b-v6m52Hw6KP8ABV69qg</recordid><startdate>202412</startdate><enddate>202412</enddate><creator>Farrash, Wesam F.</creator><creator>Idris, Shakir</creator><creator>Elzubier, Mohamed E.</creator><creator>Khidir, Elshiekh B. 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A. ; Aslam, Akhmed ; Mujalli, Abdulrahman ; Almaimani, Riyad A. ; Obaid, Ahmad A. ; El‐Readi, Mahmoud Z. ; Alobaidy, Mohammad A. ; Salaka, Afnan ; Shakoori, Afnan M. ; Saleh, Alaa M. ; Minshawi, Faisal ; Samkari, Jamil A. ; Alshehre, Sallwa M. ; Refaat, Bassem</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2789-ba9676a21175d0d1ffb73b2420f078b5f3176e612d05d577107316d6ac0f15183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Benzhydryl Compounds - pharmacology</topic><topic>Caspase</topic><topic>cholecalciferol</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - complications</topic><topic>Diabetes Mellitus, Experimental - drug therapy</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetes Mellitus, Type 2 - complications</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diet</topic><topic>Diet, High-Fat - adverse effects</topic><topic>Drug Therapy, Combination</topic><topic>Dyslipidemia</topic><topic>Fatty liver</topic><topic>Fibrosis</topic><topic>Fructose</topic><topic>Glucose</topic><topic>Glucose transporter</topic><topic>Glucosides - pharmacology</topic><topic>Glucosides - therapeutic use</topic><topic>High fat diet</topic><topic>Hydrogen peroxide</topic><topic>Hyperglycemia</topic><topic>Inflammation</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - metabolism</topic><topic>Lipids</topic><topic>Lipogenesis</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Liver diseases</topic><topic>liver fibrosis</topic><topic>Male</topic><topic>Metabolic disorders</topic><topic>Mice</topic><topic>Modulation</topic><topic>Non-alcoholic Fatty Liver Disease - drug therapy</topic><topic>Non-alcoholic Fatty Liver Disease - metabolism</topic><topic>non‐alcoholic fatty liver disease</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>PI3K/mTOR pathway</topic><topic>PTEN protein</topic><topic>SGLT2 inhibitor</topic><topic>Signal Transduction - drug effects</topic><topic>Sodium-glucose cotransporter</topic><topic>Sodium-Glucose Transporter 2 Inhibitors - pharmacology</topic><topic>Sterol regulatory element-binding protein</topic><topic>Superoxide dismutase</topic><topic>TOR protein</topic><topic>Vitamin D</topic><topic>Vitamin D - analogs & derivatives</topic><topic>Vitamin D - pharmacology</topic><topic>Vitamin D3</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Farrash, Wesam F.</creatorcontrib><creatorcontrib>Idris, Shakir</creatorcontrib><creatorcontrib>Elzubier, Mohamed E.</creatorcontrib><creatorcontrib>Khidir, Elshiekh B. A.</creatorcontrib><creatorcontrib>Aslam, Akhmed</creatorcontrib><creatorcontrib>Mujalli, Abdulrahman</creatorcontrib><creatorcontrib>Almaimani, Riyad A.</creatorcontrib><creatorcontrib>Obaid, Ahmad A.</creatorcontrib><creatorcontrib>El‐Readi, Mahmoud Z.</creatorcontrib><creatorcontrib>Alobaidy, Mohammad A.</creatorcontrib><creatorcontrib>Salaka, Afnan</creatorcontrib><creatorcontrib>Shakoori, Afnan M.</creatorcontrib><creatorcontrib>Saleh, Alaa M.</creatorcontrib><creatorcontrib>Minshawi, Faisal</creatorcontrib><creatorcontrib>Samkari, Jamil A.</creatorcontrib><creatorcontrib>Alshehre, Sallwa M.</creatorcontrib><creatorcontrib>Refaat, Bassem</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of experimental pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Farrash, Wesam F.</au><au>Idris, Shakir</au><au>Elzubier, Mohamed E.</au><au>Khidir, Elshiekh B. A.</au><au>Aslam, Akhmed</au><au>Mujalli, Abdulrahman</au><au>Almaimani, Riyad A.</au><au>Obaid, Ahmad A.</au><au>El‐Readi, Mahmoud Z.</au><au>Alobaidy, Mohammad A.</au><au>Salaka, Afnan</au><au>Shakoori, Afnan M.</au><au>Saleh, Alaa M.</au><au>Minshawi, Faisal</au><au>Samkari, Jamil A.</au><au>Alshehre, Sallwa M.</au><au>Refaat, Bassem</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction‐associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways</atitle><jtitle>International journal of experimental pathology</jtitle><addtitle>Int J Exp Pathol</addtitle><date>2024-12</date><risdate>2024</risdate><volume>105</volume><issue>6</issue><spage>219</spage><epage>234</epage><pages>219-234</pages><issn>0959-9673</issn><issn>1365-2613</issn><eissn>1365-2613</eissn><abstract>Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose‐transporting and lipid‐regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co‐therapy against diabetes‐induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti‐inflammatory, anti‐oxidative, and anti‐fibrotic pathways.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>39397269</pmid><doi>10.1111/iep.12519</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-4267-1016</orcidid><orcidid>https://orcid.org/0000-0002-6911-9179</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0959-9673 |
| ispartof | International journal of experimental pathology, 2024-12, Vol.105 (6), p.219-234 |
| issn | 0959-9673 1365-2613 1365-2613 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3116336194 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Animals Apoptosis Benzhydryl Compounds - pharmacology Caspase cholecalciferol Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - complications Diabetes Mellitus, Experimental - drug therapy Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Diet Diet, High-Fat - adverse effects Drug Therapy, Combination Dyslipidemia Fatty liver Fibrosis Fructose Glucose Glucose transporter Glucosides - pharmacology Glucosides - therapeutic use High fat diet Hydrogen peroxide Hyperglycemia Inflammation Inflammation - drug therapy Inflammation - metabolism Lipids Lipogenesis Liver Liver - drug effects Liver - metabolism Liver - pathology Liver diseases liver fibrosis Male Metabolic disorders Mice Modulation Non-alcoholic Fatty Liver Disease - drug therapy Non-alcoholic Fatty Liver Disease - metabolism non‐alcoholic fatty liver disease Oxidative stress Oxidative Stress - drug effects PI3K/mTOR pathway PTEN protein SGLT2 inhibitor Signal Transduction - drug effects Sodium-glucose cotransporter Sodium-Glucose Transporter 2 Inhibitors - pharmacology Sterol regulatory element-binding protein Superoxide dismutase TOR protein Vitamin D Vitamin D - analogs & derivatives Vitamin D - pharmacology Vitamin D3 |
| title | Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction‐associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways |
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