RESUMO
Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Masculino , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR alfa/genética , Ácidos e Sais Biliares , Citoplasma , Camundongos Knockout , Ácidos GraxosRESUMO
Stimulation of adipose tissue thermogenesis is regarded as a promising avenue in the treatment of obesity. However, pharmacologic engagement of this process has proven difficult. Using the Connectivity Map (CMap) approach, we identified the phytochemical hyperforin (HPF) as an anti-obesity agent. We found that HPF efficiently promoted thermogenesis by stimulating AMPK and PGC-1α via a Ucp1-dependent pathway. Using LiP-SMap (limited proteolysis-mass spectrometry) combined with a microscale thermophoresis assay and molecular docking analysis, we confirmed dihydrolipoamide S-acetyltransferase (Dlat) as a direct molecular target of HPF. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo. Furthermore, genome-wide association study analysis indicated that a variation in DLAT is significantly associated with obesity in humans. These findings suggest that HPF is a promising lead compound in the pursuit of a pharmacological approach to promote energy expenditure in the treatment of obesity.
Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Floroglucinol/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Terpenos/farmacologia , Termogênese/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Sítios de Ligação , Temperatura Baixa , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/química , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/metabolismo , Humanos , Hypericum/química , Hypericum/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Floroglucinol/química , Floroglucinol/metabolismo , Floroglucinol/farmacologia , Floroglucinol/uso terapêutico , Terpenos/química , Terpenos/metabolismo , Terpenos/uso terapêutico , Termogênese/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Qi-Jing-Sheng-Bai granule is an effective traditional Chinese medicine formula that has been widely used for the treatment of leukopenia post radiotherapy or chemotherapy. However, its chemical constituents were still unclear, which hindered interpreting bioactive constituents and studying integrative mechanisms. In this study, we developed a three-step strategy to characterize the chemical constituents and metabolites of Qi-Jing-Sheng-Bai by using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. As a result, a total of 143 compounds, including 56 flavonoids, 51 saponins, and 36 other compounds, of which contained six pairs of isomers, were tentatively identified and characterized via reference standards and by comparing mass spectrometry data with literature. After oral administration of 15 g/kg Qi-Jing-Sheng-Bai, a number of 42 compounds including 24 prototype compounds and 18 metabolites have been detected in the serum of rats. This work serves as the first reference for Qi-Jing-Sheng-Bai chemical components and metabolites. Moreover, it provided a rapid and valid analytical strategy for characterization of the chemical compounds and metabolites of traditional Chinese medicine formula.