Mazdutide Ameliorates Non-Alcoholic Fatty Liver Disease by Modulating Endoplasmic Reticulum Stress
This preclinical study investigated whether mazdutide — a dual GLP-1/glucagon receptor agonist that has shown clinical promise for weight management and metabolic disorders — could alleviate non-alcoholic fatty liver disease (NAFLD) and explored its potential mechanism of action. Researchers induced NAFLD in mice via a 12-week high-fat diet, then treated animals with subcutaneous mazdutide for four weeks. Complementary in vitro experiments exposed hepatocytes to free fatty acids to model hepatic steatosis, followed by mazdutide co-treatment. The study measured serum and liver lipid profiles, liver injury markers, inflammatory cytokines, oxidative stress indicators, and key protein expression via Western blot and immunohistochemistry. Results indicated that mazdutide treatment was associated with reduced hepatic fat accumulation, lower liver injury markers, attenuated inflammation, and decreased oxidative stress in both models. Mechanistically, the authors attributed these effects to modulation of the PERK–eIF2α–ATF4–CHOP endoplasmic reticulum (ER) stress pathway, suppression of NF-κB-driven inflammation, and downregulation of lipogenic regulators (SREBP-1, C/EBPβ, PPARγ). Key limitations include the exclusive use of animal and cell-based models, lack of human data, and preprint status meaning findings have not yet undergone formal peer review.
Why this grade: All experimental work was conducted in a mouse high-fat diet model and cultured hepatocytes, with no human participants enrolled, and the manuscript has not yet been peer-reviewed.
Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder globally. Mazdutide has shown clinical benefits in weight management and metabolic regulation, indicating its potential as a therapeutic agent for NAFLD. This study aimed to investigate the efficacy and mechanism of action of Mazdutide against early-stage NAFLD. Methods: A NAFLD mouse model was induced by a 12-week high-fat diet, followed by a 4-week treatment with subcutaneous Mazdutide (100, 200, or 400 μg/kg). In vitro, a cellular NAFLD model was established by treating hepatocytes with 1 mM free fatty acids for 24 h, followed by co-treatment with Mazdutide (10, 20, or 50 nM) or the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid (4-PBA). Serum and hepatic lipid profiles, liver injury markers, and pro-inflammatory cytokines were quantified. Liver histopathology was assessed by hematoxylin and eosin and Oil Red O staining. Protein expression related to ER stress, inflammation, and lipid metabolism was analyzed by immunohistochemistry and Western blot. Results: Mazdutide treatment significantly ameliorated systemic and hepatic lipid metabolism disorders, reduced liver injury markers and hepatic steatosis, and mitigated inflammation and oxidative stress in NAFLD mice and hepatocytes. Mechanistically, Mazdutide alleviated ER stress by modulating the PERK-eIF2α-ATF4-CHOP pathway, suppressed the NF-κB-mediated inflammatory response, and downregulated key lipogenic regulators, including SREBP-1, C/EBPβ, and PPARγ. Conclusion: Our findings demonstrate that Mazdutide alleviates hepatic ER stress in NAFLD, leading to suppressed inflammatory responses and improved lipid metabolism, which ultimately attenuates disease progression.
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