Zhimu-Huangbai herb-pair ameliorates hepatic steatosis in mice by regulating IRE1α/XBP1s pathway to inhibit SREBP-1c
Abstract
BACKGROUND: Currently, there is a lack of validated pharmacological interventions for non-alcoholic fatty liver disease (NAFLD), which is characterized by the accumulation of hepatic triglyceride. Zhimu-Huangbai (ZH) herb-pair is a traditional Chinese medicine that regulates glucose and lipid metabolism disorders. However, the precise mechanisms underlying the preventive effects of hepatic triglyceride induced by high-fat diet (HFD) remain elusive.
PURPOSE: The study aimed to examine the impact of ZH herb-pair on NAFLD in mice and explore the underlying mechanisms, particularly its effects on endoplasmic reticulum (ER) stress and lipid metabolism.
METHODS: NAFLD was induced in mice using HFD, and the treated mice were orally administered ZH, metformin (Glucophage) or lovastatin. The lipid metabolism factors, ER stress markers, and the unfolded protein response (UPR) branch factors were measured using immunohistochemistry, western blotting or qRT-PCR. Co-Immunoprecipitation (CoIP) was performed to reveal the connection between SCAP and SREBP-1c. Tunicamycin (TM) and plasmid delivery were used to induce acute ER stress or crease XBP1 gain function models. The main compounds in ZH binding to IRE1α protein were studied by molecular docking and cellular thermal shift assay (CETSA).
RESULTS: Treatment with ZH significantly ameliorated hepatic steatosis and reduced lipid synthesis process mainly inhibiting the expression of mature active form of SREBP-1c through relieving ER…
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