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Oleuropein-Rich Jasminum Grandiflorum Flower Extract Regulates the LKB1-PGC-1α Axis Related to the Attenuation of Hepatocellular Lipid Dysmetabolism.

ABSTRACT: Diets() rich in fat are a major() cause() of metabolic disease(), and nutritional() food has been widely() used() to counteract the metabolic disorders such() as obesity() and fatty() liver(). The present study investigated the effects of oleuropein-enriched extract() from Jasminum grandiflorum L. flowers (OLE-JGF) in high-fat diet() (HFD)-fed mice and oleic acid() (OA)-treated AML-12 cells. Treatment() of HFD-fed mice with 0.6% OLE-JGF for 8 weeks significantly reduced body and liver() weights, as well as attenuating lipid dysmetabolism and hepatic steatosis. OLE-JGF administration() prominently suppressed the mRNA expressions() of monocyte chemoattractant protein()-1 (MCP-1) and cluster of differentiation 68 (CD68), and it also downregulated acetyl-CoA carboxylase (ACC) and fatty() acid() synthase (FAS) as well as sterol-regulatory-element()-binding protein() (SREBP-1c) in the liver(). Meanwhile, mitochondrial DNA and uncoupling protein() 2 (UCP2) were upregulated along with the increased expression() of mitochondrial biogenic promoters including liver() kinase B1 (LKB1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear() factor()-erythroid-derived 2-like 2 (Nrf2), and mitochondrial transcription factor() A (Tfam), but did not change AMP-activated protein() kinase (AMPK) in liver(). The lipid droplets were decreased significantly after treatment() with 80 μM oleuropein for 24 h in OA-induced AML-12 cells. Furthermore, oleuropein significantly inhibited ACC mRNA expression() and upregulated LKB1, PGC-1α, and Tfam mRNA levels, as well as increasing the binding level of LKB1 to PGC-1α promoter in OA-induced cells. These findings indicate() that OLE-JGF reduces hepatic lipid deposition in HFD-fed mice, as well as the fact that OA-induced liver() cells may be partly() attributed to upregulation of the LKB1-PGC-1α axis, which mediates hepatic lipogenesis and mitochondrial biogenesis. Our study provides a scientific() basis() for the benefits and potential() use() of the J. grandiflorum flower as a food supplement() for the prevention() and treatment() of metabolic disease().

SUBMITTER: Hou Y

PROVIDER: S-EPMC10780778 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Oleuropein-Rich Jasminum Grandiflorum Flower Extract Regulates the LKB1-PGC-1α Axis Related to the Attenuation of Hepatocellular Lipid Dysmetabolism.

Hou Yajun Y Zhao Xuan X Wang Yalin Y Li Yapeng Y Chen Caihong C Zhou Xiu X Jin Jingwei J Ye Jiming J Li Dongli D Gan Lishe L Wu Rihui R

Nutrients 20231224 1

Diets() rich in fat are a major() cause() of metabolic disease(), and nutritional() food has been widely() used() to counteract the metabolic disorders such() as obesity() and fatty() liver(). The present study investigated the effects of oleuropein-enriched extract() from <i>Jasminum grandiflorum</i> L. flowers (OLE-JGF) in high-fat diet() (HFD)-fed mice and oleic acid() (OA)-treated AML-12 cells. Treatment() of HFD-fed mice with 0.6% OLE-JGF for 8 weeks significantly reduced body and liver() w ...[more]

PMID: 38201888

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Project description:UnlabelledHepatitis C virus (HCV) causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). Wild-type peroxisome proliferator-activated receptor gamma coactivator 1 alpha (WT-PGC-1α) is essential in hepatic gluconeogenesis and has recently been demonstrated to link HCV infection to hepatic insulin resistance (IR). A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV modulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. The upregulation of both PGC-1α isoforms depended on HCV RNA replication. By using promoter-luciferase reporters, kinase inhibitors, and dominant negative mutants, we further observed that the HCV-induced upregulation of WT-PGC-1α was mediated by the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1α was mediated by CREB phosphorylation and forkhead box O1 dephosphorylation. Moreover, HCV infection induced endoplasmic reticulum (ER) stress, and pharmacological induction of ER stress upregulated WT-PGC-1α/L-PGC-1α and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1α/L-PGC-1α upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1α with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1α and L-PGC-1α through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1α isoforms promote HCV production in turn.ImportanceHCV causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). As a key regulator in energy metabolism, wild-type PGC-1α (WT-PGC-1α), has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV regulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. WT-PGC-1α upregulation was mediated by CREB phosphorylation, whereas L-PGC-1α upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1α/L-PGC-1α upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1α/L-PGC-1α and highlights the novel intervention of HCV-ER stress-PGC-1α signaling for HCV therapy and HCV-induced IR therapy.

Dataset Information

Oleuropein-Rich Jasminum Grandiflorum Flower Extract Regulates the LKB1-PGC-1α Axis Related to the Attenuation of Hepatocellular Lipid Dysmetabolism.

Publications

Oleuropein-Rich Jasminum Grandiflorum Flower Extract Regulates the LKB1-PGC-1α Axis Related to the Attenuation of Hepatocellular Lipid Dysmetabolism.

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