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

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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Bibliographic Details
Published in:International journal of experimental pathology Vol. 105; no. 6; pp. 219 - 234
Main Authors: 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
Format: Journal Article
Language:English
Published: England Wiley Subscription Services, Inc 01-12-2024
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Apoptosis
Caspase
cholecalciferol
Diabetes
Diabetes mellitus
Diet
Dyslipidemia
Fatty liver
Fibrosis
Fructose
Glucose
Glucose transporter
High fat diet
Hydrogen peroxide
Hyperglycemia
Inflammation
Lipids
Lipogenesis
Liver
Liver diseases
liver fibrosis
Metabolic disorders
Modulation
non‐alcoholic fatty liver disease
Oxidative stress
PI3K/mTOR pathway
PTEN protein
SGLT2 inhibitor
Sodium-glucose cotransporter
Sterol regulatory element-binding protein
Superoxide dismutase
TOR protein
Vitamin D
Vitamin D3
cholecalciferol
liver fibrosis
PI3K/mTOR pathway
non‐alcoholic fatty liver disease
SGLT2 inhibitor
oxidative stress
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Summary: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.
Bibliography:Wesam F. Farrash and Bassem Refaat are joint first author.
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0959-9673
1365-2613
1365-2613
DOI:10.1111/iep.12519