Suppression of oxidative stress and improvement of liver functions in mice by ursolic acid via <scp>LKB</scp>1‐<scp>AMP</scp>‐activated protein kinase signaling

Yang, Yongbin; Zhao, Zhanxue; Liu, Yuanjun; Kang, Xianjiang; Zhang, Haisong; Mao, Meng

doi:10.1111/jgh.12723

Cited by 45 publications

(28 citation statements)

References 40 publications

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“…Acetylcholine also provides cardioprotection against hypoxia/reoxygenation injury in a cellular model through an AMPK/PGC1‐ α ‐involved mechanism that increases mitochondrial density, mass, and mtDNA copy number . In a variety of experimental liver fibrosis models, curcumin , adiponectin , and ursolic acids have been utilized to exert protective effects via LKB1‐AMPK signaling activation. Moreover, melatonin was recently shown to improve steatotic liver graft preservation via AMPK‐mediated autophagy activation .…”

Section: Discussionmentioning

confidence: 99%

Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride‐induced liver fibrosis

Kang

Hong

Lee

2016

Journal of Pineal Research

200

161

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Liver fibrosis leads to liver cirrhosis and failure, and no effective treatment is currently available. Growing evidence supports a link between mitochondrial dysfunction and liver fibrogenesis and mitochondrial quality control-based therapy has emerged as a new therapeutic target. We investigated the protective mechanisms of melatonin against mitochondrial dysfunction-involved liver fibrosis, focusing on mitophagy and mitochondrial biogenesis. Rats were treated with carbon tetrachloride (CCl4) dissolved in olive oil (0.5 mL/kg, twice a week, i.p.) for 8 wk. Melatonin was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 exposure induced collagen deposition, hepatocellular damage, and oxidative stress, and melatonin attenuated these increases. Increases in mRNA and protein expression levels of transforming growth factor β1 and α-smooth muscle actin in response to CCl4 were attenuated by melatonin. Melatonin attenuated hallmarks of mitochondrial dysfunction, such as mitochondrial swelling and glutamate dehydrogenase release. Chronic CCl4 exposure impaired mitophagy and mitochondrial biogenesis, and melatonin attenuated this impairment, as indicated by increases in mitochondrial DNA and in protein levels of PTEN-induced putative kinase 1 (PINK1); Parkin; peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α); nuclear respiratory factor 1 (NRF1); and transcription factor A, mitochondrial (TFAM). CCl4-mediated decreases in mitochondrial fission- and fusion-related proteins, such as dynamin-related protein 1 (DRP1) and mitofusin 2, were also attenuated by melatonin. Moreover, melatonin induced AMP-activated protein kinase (AMPK) phosphorylation. These results suggest that melatonin protects against liver fibrosis via upregulation of mitophagy and mitochondrial biogenesis, and may be useful as an anti-fibrotic treatment.

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Section: Discussionmentioning

confidence: 99%

Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride‐induced liver fibrosis

Kang

Hong

Lee

2016

Journal of Pineal Research

200

161

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“…It is well‐accepted that the crucial proteins, including CD36 and CPT‐1, which are in charge of mediating FFA uptake and oxidation, are regulated by AMPK activation . Studies have reported that AMPK activation is involved in UA‐induced apoptosis of cancer and improvement of liver function . However, whether and how AMPK pathway mediates UA‐stimulated skeletal muscle FFA catabolism is also not well identified so far.…”

Section: Discussionmentioning

confidence: 99%

Ursolic acid increases energy expenditure through enhancing free fatty acid uptake and β‐oxidation via an UCP3/AMPK‐dependent pathway in skeletal muscle

Chu

Shi

et al. 2015

Molecular Nutrition Food Res

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“…There is increasing evidence showing a beneficial role of AMPK activation in reducing hepatic fibrosis, improving liver function, and lowering hepatocytotoxicity (Liang et al, 2017). In addition, several novel drug candidates for the treatment of hepatic fibrosis, including metformin, betulin, berberine, cucurbitacin E, and curcumin, have been shown to act via increased AMPK signaling (Xu et al, 2003;Fu et al, 2008;Yang et al, 2015;Wu et al, 2016;Liang et al, 2017). Moreover, AMPK signaling is known to negatively regulate mTOR, an atypical serine/threonine kinase shown to play an important role in the regulation of cell growth, differentiation, migration, and survival through transcription factors S6K1, 4EBP1, and PPARg.…”

Section: Pbi-4050 Reduces Liver Fibrosismentioning

confidence: 99%

PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

Grouix¹,

Sarra‐Bournet²,

Leduc³

et al. 2018

J Pharmacol Exp Ther

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Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently no effective therapy. We previously showed that 2-(3-pentylphenyl)acetic acid (PBI-4050) is a dual G protein-coupled receptor GPR40 agonist/GPR84 antagonist that exerts antifibrotic, anti-inflammatory, and antiproliferative action. We evaluated PBI-4050 for the treatment of liver fibrosis in vivo and elucidated its mechanism of action on human hepatic stellate cells (HSCs). The antifibrotic effect of PBI-4050 was evaluated in carbon tetrachloride (CCl)- and bile duct ligation-induced liver fibrosis rodent models. Treatment with PBI-4050 suppressed CCl-induced serum aspartate aminotransferase levels, inflammatory marker nitric oxide synthase, epithelial to mesenchymal transition transcription factor Snail, and multiple profibrotic factors. PBI-4050 also decreased GPR84 mRNA expression in CCl-induced injury, while restoring peroxisome proliferator-activated receptor (PPAR) to the control level. Collagen deposition and -smooth muscle actin (-SMA) protein levels were also attenuated by PBI-4050 treatment in the bile duct ligation rat model. Transforming growth factor--activated primary HSCs were used to examine the effect of PBI-4050 and its mechanism of action in vitro. PBI-4050 inhibited HSC proliferation by arresting cells in the G0/G1 cycle phase. Subsequent analysis demonstrated that PBI-4050 signals through a reduction of intracellular ATP levels, activation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), and blockade of mammalian target of rapamycin (mTOR), resulting in reduced protein and mRNA levels of -SMA and connective tissue growth factor and restored PPAR mRNA expression. Our findings suggest that PBI-4050 may exert antifibrotic activity in the liver through a novel mechanism of action involving modulation of intracellular ATP levels and the LKB1/AMPK/mTOR pathway in stellate cells, and PBI-4050 may be a promising agent for treating liver fibrosis.

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Suppression of oxidative stress and improvement of liver functions in mice by ursolic acid via LKB1‐AMP‐activated protein kinase signaling

Abstract: UA via LKB1-AMPK signaling offers protective effects on BDL-induced liver injury in mice, which may be related to inhibition of oxidative stress.

Cited by 45 publications

References 40 publications

Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride‐induced liver fibrosis

Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride‐induced liver fibrosis

Ursolic acid increases energy expenditure through enhancing free fatty acid uptake and β‐oxidation via an UCP3/AMPK‐dependent pathway in skeletal muscle

PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

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