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Chlorogenic Acid Inhibits Ceramide Accumulation to Restrain Hepatic Glucagon Response.

ABSTRACT: Chlorogenic acid (CGA), a dietary natural phenolic acid, has been widely reported to regulate glucose and lipid metabolism. However, the protective effects and the underlying mechanisms of CGA on glucagon-induced hepatic glucose production remain largely uncharacterized. Herein, we investigated the efficacy of CGA on hepatic gluconeogenesis both in vivo and in vitro. The elevated levels of endogenous glucose production induced by infusion of glucagon or pyruvate were lowered in mice administered with CGA. Furthermore, chronic CGA treatment ameliorated the accumulation of glucose and ceramide in high-fat diet (HFD)-fed mice. CGA also attenuated HFD-fed-induced inflammation response. The protective effect of CGA on glucose production was further confirmed in primary mouse hepatocytes by inhibiting accumulation of ceramide and expression of p38 MAPK. Moreover, CGA administration in HFD-fed mice preserved the decreased phosphorylation of Akt in the liver, resulting in the inhibition of FoxO1 activation and, ultimately, hepatic gluconeogenesis. However, these protective effects were significantly attenuated by the addition of C2 ceramide. These results suggest that CGA inhibits ceramide accumulation to restrain hepatic glucagon response.

SUBMITTER: Xiao N

PROVIDER: S-EPMC10384019 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Chlorogenic Acid Inhibits Ceramide Accumulation to Restrain Hepatic Glucagon Response.

Xiao Na N Zhang Tengfei T Han Mingli M Tian Dan D Liu Jiawei J Li Shan S Yang Lele L Pan Guojun G

Nutrients 20230717 14

Chlorogenic acid (CGA), a dietary natural phenolic acid, has been widely reported to regulate glucose and lipid metabolism. However, the protective effects and the underlying mechanisms of CGA on glucagon-induced hepatic glucose production remain largely uncharacterized. Herein, we investigated the efficacy of CGA on hepatic gluconeogenesis both in vivo and in vitro. The elevated levels of endogenous glucose production induced by infusion of glucagon or pyruvate were lowered in mice administered ...[more]

PMID: 37513589

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Project description:BackgroundGongju is recognized as one of the four traditional Chinese medicinal herbs, and its main constituents are chlorogenic acid (CGA) and its derivative material. CGA content in autooctoploid Gongju are considerably elevated compared with those in parental tetraploid Gongju at different flowering stages. However, the underlying molecular mechanisms governing the regulation CGA content remain poorly understood.MethodsTherefore, we conducted integrated transcriptome and metabolome analyses of different flowering stages in autooctoploid and tetraploid Gongju to elucidate the underlying molecular mechanisms governing CGA biosynthesis.ResultsTranscriptome analysis showed that the number of differentially expressed genes in the budding stage (BS), early flowering stage (EF), and full flowering stage (FF) of tetraploid and octoploid Gongju were 3859, 11,211, and 6837, respectively. A total of 563, 466, and 394 differential accumulated metabolites were respectively identified between the bud stages of tetraploid and octoploid Gongju (4BS vs. 8BS), between the early flowering stages of tetraploid and octoploid Gongju (4EF vs. 8EF), and the full flowering stages of tetraploid and octoploid Gongju (4FF vs. 8FF) groups. The integrated analysis of transcriptomics and metabolomics revealed that the expression of pma6460 and mws0178, which are key enzymes involved in the CGA synthesis pathway, increased during the flowering stages of octoploid Gongju relative to that of tetraploid Gongju. The expression levels of CmHQT and CmC3H genes associated with CGA synthesis were higher in octoploid plants than in tetraploid plants at various flowering stages. To investigate the potential regulation of transcription factors involved in CGA synthesis, we analyzed the coexpression of CmC3H and CmHQT with CmMYBs and CmbHLHs. Results indicated that transcription factors, such as CmMYB12 (Cluster-30519.0), CmMYB26 (Cluster-75874.0), CmMYB5 (Cluster-94106.0), CmMYB1 (Cluster-71968.7), CmbHLH62 (Cluster-32024.1), CmbHLH75 (Cluster-62341.0), CmbHLH62 (Cluster-32024.8), CmbHLH75 (Cluster-60210.0), and CmbHLH16 (Cluster-90665.1) play a pivotal role in CGA synthesis regulation. The present study provides novel insights into the molecular mechanisms underlying CGA accumulation in autopolyploid Gongju.

Project description:Chlorogenic acid (CGA) is a phenolic compound with well-known antibacterial properties against pathogens. In this study, structural and biochemical characterization was used to show the inhibitory role of CGA against the enzyme of the shikimate pathway, a well-characterized drug target in several pathogens. Here, we report the crystal structures of dehydroquinate synthase (DHQS), the second enzyme of the shikimate pathway, from Providencia alcalifaciens (PaDHQS), in binary complex with NAD and ternary complex with NAD and CGA. Structural analyses reveal that CGA occupies the substrate position in the active site of PaDHQS, which disables domain movements, leaving the enzyme in an open and catalysis-incompetent state. The binding analyses by isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) show that CGA binds to PaDHQS with KD (equilibrium dissociation constant) values of 6.3 μM and 0.5 μM, respectively. In vitro enzyme inhibition studies show that CGA inhibits PaDHQS with a Ki of 235 ± 21 μM, while it inhibits the growth of Providencia alcalifaciens, Moraxella catarrhalis, Staphylococcus aureus, and Escherichia coli with MIC values of 60 to 100 μM. In the presence of aromatic amino acids supplied externally, CGA does not show the toxic effect. These results, along with the observations of the inhibition of the 3-deoxy-d-arabino-heptulosonate-7-phosphate (DAHP) regulatory domain by CGA in our previous study, suggest that CGA binds to shikimate pathway enzymes with high affinity and inhibits their catalysis and can be further exploited for designing novel drug-like molecules.IMPORTANCE The shikimate pathway is an attractive target for the development of herbicides and antimicrobial agents, as it is essential in plants, bacteria, and apicomplexan parasites but absent in humans. The enzymes of shikimate pathway are conserved among bacteria. Thus, the inhibitors of the shikimate pathway act on wide range of pathogens. We have identified that chlorogenic acid targets the enzymes of the shikimate pathway. The crystal structure of dehydroquinate synthase, the second enzyme of the pathway, in complex with chlorogenic acid and enzymatic inhibition studies explains the mechanism of inhibition of chlorogenic acid. These results suggest that chlorogenic acid has a good chemical scaffold and have important implications for its further development as a potent inhibitor of shikimate pathway enzymes.

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Chlorogenic Acid Inhibits Ceramide Accumulation to Restrain Hepatic Glucagon Response.

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Chlorogenic Acid Inhibits Ceramide Accumulation to Restrain Hepatic Glucagon Response.

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