Dataset Information

Vutiglabridin Modulates Paraoxonase 1 and Ameliorates Diet-Induced Obesity in Hyperlipidemic Mice.

ABSTRACT: Vutiglabridin is a clinical-stage synthetic small molecule that is being developed for the treatment of obesity and its target proteins have not been fully identified. Paraoxonase-1 (PON1) is an HDL-associated plasma enzyme that hydrolyzes diverse substrates including oxidized low-density lipoprotein (LDL). Furthermore, PON1 harbors anti-inflammatory and antioxidant capacities and has been implicated as a potential therapeutic target for treating various metabolic diseases. In this study, we performed a non-biased target deconvolution of vutiglabridin using Nematic Protein Organisation Technique (NPOT) and identified PON1 as an interacting protein. We examined this interaction in detail and demonstrate that vutiglabridin binds to PON1 with high affinity and protects PON1 against oxidative damage. Vutiglabridin treatment significantly increased plasma PON1 levels and enzyme activity but not PON1 mRNA in wild-type C57BL/6J mice, suggesting that vutiglabridin modulates PON1 post-transcriptionally. We further investigated the effects of vutiglabridin in obese and hyperlipidemic LDLR^-/- mice and found that it significantly increases plasma PON1 levels, while decreasing body weight, total fat mass, and plasma cholesterol levels. Overall, our results demonstrate that PON1 is a direct, interacting target of vutiglabridin, and that the modulation of PON1 by vutiglabridin may provide benefits for the treatment of hyperlipidemia and obesity.

SUBMITTER: Sulaiman D

PROVIDER: S-EPMC10135725 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Vutiglabridin Modulates Paraoxonase 1 and Ameliorates Diet-Induced Obesity in Hyperlipidemic Mice.

Sulaiman Dawoud D Choi Leo Sungwong LS Lee Hyeong Min HM Shin Jaejin J Kim Dong Hwan DH Lee Keun Woo KW Eftekhari Pierre P Quartier Angélique A Park Hyung Soon HS Reddy Srinivasa T ST

Biomolecules 20230418 4

Vutiglabridin is a clinical-stage synthetic small molecule that is being developed for the treatment of obesity and its target proteins have not been fully identified. Paraoxonase-1 (PON1) is an HDL-associated plasma enzyme that hydrolyzes diverse substrates including oxidized low-density lipoprotein (LDL). Furthermore, PON1 harbors anti-inflammatory and antioxidant capacities and has been implicated as a potential therapeutic target for treating various metabolic diseases. In this study, we per ...[more]

PMID: 37189434

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Project description:Brown adipose tissue (BAT) is a critical regulator of non-shivering thermogenesis and energy expenditure, offering significant potential for addressing obesity and associated metabolic disorders. Isoliquiritigenin (ISL), a natural flavonoid, has shown promising therapeutic effects in lipid metabolism-related diseases. This study aimed to explore the effects of ISL on lipid metabolism and obesity using a high-fat-diet (HFD)-induced obesity model in mice. Mice were subjected to an HFD and treated with ISL via gavage. The results demonstrated that ISL treatment significantly reduced HFD-induced weight gain and upregulated the expression of key thermogenic genes, suggesting enhanced BAT activity and thermogenesis. In vitro experiments using C3H10-T1/2 cells further supported these findings, as ISL treatment markedly increased the expression of UCP1 and PPARGC1a, which are critical regulators of thermogenesis. To elucidate the molecular mechanisms underlying ISL's effects, we conducted a transcriptomic analysis of BAT from ISL-treated mice. Pathway enrichment analysis revealed that differentially expressed genes were predominantly associated with metabolic processes, including the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and fatty acid degradation. These pathways are integral to energy metabolism and thermogenesis, providing mechanistic insights into ISL's anti-obesity effects. Additionally, ISL treatment significantly downregulated the expression of NNAT and SGK1, genes implicated in lipid metabolism and energy homeostasis. These findings suggest that ISL modulates BAT function by regulating the expression of these genes, thereby influencing lipid deposition and thermogenic capacity. In summary, this study suggests that ISL treatment has the potential to mitigate HFD-induced obesity by promoting BAT thermogenesis and modulating lipid metabolism. The molecular mechanisms involve the regulation of key metabolic pathways and genes, such as NNAT and SGK1, highlighting ISL's potential as a therapeutic agent for obesity and related metabolic disorders.

Dataset Information

Vutiglabridin Modulates Paraoxonase 1 and Ameliorates Diet-Induced Obesity in Hyperlipidemic Mice.

Publications

Vutiglabridin Modulates Paraoxonase 1 and Ameliorates Diet-Induced Obesity in Hyperlipidemic Mice.

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