7'-Hydroxyl Substituted Xanthones from Gentianella Acuta Revert Hepatic Steatosis in Obese Diabetic Mice Through Preserving Mitochondrial Homeostasis

Abstract

Mitochondrial dysfunction has been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Xanthones, bioactive flavonoids derived from various herbal medicines, are known for their antioxidant, anti-inflammatory, and anti-tumor properties. This study aimed to elucidate the effects of xanthones isolated from Gentianella acuta on hepatic steatosis and the underlying mechanisms regulating mitochondrial function. We report that a xanthone fraction (400 mg/kg/day) effectively prevented obesity and hepatic steatosis in obese diabetic db/db mice in vivo. In vitro, xanthones inhibited lipid accumulation and mitochondrial dysfunction induced by high glucose (20 mM) and high palmitic acid (200 µM) in HepG2 cells. Mechanistically, norathyriol (NTR), a major in vivo metabolite of Gentianella acuta, inhibited the activity of dynamin-related protein 1 (Drp1), which is associated with mitochondrial fission, and prevented its translocation from the cytoplasm to the mitochondria by inhibiting the orphan nuclear receptor subfamily 4 group A member (Nur77). Additionally, NTR increased the expression of the mitochondrial outer membrane protein FUN14 domain containing 1 (FUNDC1), which stimulated mitophagy to clear damaged or dysfunctional mitochondria under conditions of overnutrition. We also discovered that reactive oxygen species targeted FUNDC1, leading to mitochondrial damage, which could be reversed by 7'-hydroxyl substituted xanthones. Collectively, 7'-hydroxyl substituted xanthones inhibited mitochondrial fission while promoting mitophagy, ultimately improving mitochondrial and liver function in the context of diabetic hepatic steatosis. The modulation of mitochondrial function by 7'-hydroxyl substituted xanthones presents a novel approach for treating hepatic steatosis, particularly in diabetic conditions.

Note:
Funding declaration: This work was supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No: ZYYCXTD-C-202009), Tianjin Municipal Health Commission Project (No. 2024009), and Xinjiang Uygur Autonomous Region Science and Technology Program Project (No. 2022LQ04007).

Conflict of Interests: The authors declare no conflict of interest.

Ethical Approval: All animal experiments were approved by Tianjin University of Traditional Chinese Medicine Committee on Use and Care of Animals (TCM-LAEC20170027).

Keywords: Xanthones, hepatic steatosis, mitochondrial dysfunction, nuclear receptor Nur77, FUN14 domain containing 1