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Paraxonase-2 agonist, Vutiglabridin alleviates non-alcoholic steatohepatitis via autophagy activation

ABSTRACT: Limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH), a common immunometabolic disease. Glabridin, a novel anti-obesity candidate, is not druggable due to low in vivo chemical stability and bioavailability. We developed vutiglabridin (VUTI) and investigated therapeutic effects, molecular targets, and mechanisms of action in NASH. VUTI was therapeutically administrated in amylin-NASH, high fat-diet induced obesity, and thioacetamide-induced hepatic fibrosis mouse models. The mechanism of action of VUTI was studied using RNA sequencing, lipidome, and proteome analyses using mouse tissues. VUTI alleviated hepatic steatosis, fibrosis, and inflammation. Lipidome analysis revealed that VUTI affects the various individual lipid profiles. VUTI exerted therapeutic effects by increasing lipid catabolism, activating autophagy, and reducing mitochondrial oxidative stress, thus mitigating NASH pathogenesis. The cellular target of VUTI was paraoxonase-2 identified using chemical proteome analysis, which promotes its enzyme activity to enhance autophagy activation. VUTI, as a paraoxonase-2 agonist, mitigates all aspects of NASH and may be a promising therapeutic alternative for NASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE222659 | GEO | 2024/01/15

REPOSITORIES: GEO

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Project description:Background & Aims: In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, the main determinant of NASH-associated mortality. The short chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remains unclear. Methods: Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic NASH-inducing diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared to an HFD control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). Results: HFD-fed mice developed obesity, insulin resistance, increased levels of plasma leptin, adipose tissue inflammation, gut permeability, dysbiosis and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI-1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways RhoA/Rock and PI3K/AKT and other important pro-fibrotic regulators (e.g. YAP/TAZ and MYC) by butyrate, providing a potential rationale for its antifibrotic effects. Conclusions: Butyrate protects against the development of obesity and insulin resistance-associated NASH and liver fibrosis. These antifibrotic effects are at least in part attributable to a direct effect on collagen production in hepatic stellate cells, as a result of inhibiting non-canonical TGF-β signaling.

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Paraxonase-2 agonist, Vutiglabridin alleviates non-alcoholic steatohepatitis via autophagy activation

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