Melatonin suppresses activation of hepatic stellate cells through <scp>ROR</scp><i>α</i>‐mediated inhibition of 5‐lipoxygenase

Shajari, Shiva; Laliena, Almudena; Heegsma, Janette; Tuñón, María J.; Moshage, Han; Faber, Klaas Nico

doi:10.1111/jpi.12271

Cited by 46 publications

(40 citation statements)

References 58 publications

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“…5-LOX inhibitors have been shown to increase the activation of cultured hepatic cells and increase Kupffer cell apoptosis [49, 50]. The treatment with the COX inhibitor celecoxib results in a significant reduction in fibrosis in rat models [51, 52].…”

Section: Discussionmentioning

confidence: 99%

An ω-3-enriched diet alone does not attenuate CCl 4 -induced hepatic fibrosis

Harris

Kodani

Yang

et al. 2016

The Journal of Nutritional Biochemistry

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Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl4) leads to hepatic lipid peroxidation, inflammation, and fibrosis. Dietary supplementation of ω-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ω-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl4. In this study we fed CCl4-treated mice a high ω-3 diet (using a mix of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) ethyl esters). We also co-administered an inhibitor of soluble epoxide hydrolase, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which has been shown to boost anti-inflammatory epoxy fatty acids that are produced from both ω-3 and ω-6 dietary lipids. In this study, we showed that soluble epoxide inhibitors reduced CCl4-induced liver fibrosis. Three major results were obtained. First, the ω-3 enriched diet did not attenuate CCl4-induced liver fibrosis as judged by collagen deposition and collagen mRNA expression. Second, the ω-3 enriched diet raised hepatic tissue levels of several inflammatory lipoxygenase metabolites and prostaglandins, including PGE2. Third, treatment with TPPU in drinking water in conjunction with the ω-3 enriched diet resulted in a reduction in liver fibrosis compared to all other groups. Taken together, these results indicate that dietary ω-3 supplementation alone did not attenuate CCl4-induced liver fibrosis. Additionally, oxylipin signaling molecules may play role in the CCl4-induced liver fibrosis in the high ω-3 diet groups.

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Section: Discussionmentioning

confidence: 99%

An ω-3-enriched diet alone does not attenuate CCl 4 -induced hepatic fibrosis

Harris

Kodani

Yang

et al. 2016

The Journal of Nutritional Biochemistry

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“…Several studies have suggested that melatonin might be developed into a promising treatment for liver fibrosis. In addition, some studies demonstrated that melatonin attenuated liver fibrosis via limiting the expression of profibrogenic genes [143], directly suppressing hepatic stellate cells activation [144], and so on.…”

Section: Protective Effects Of Melatonin On Liver Fibrosismentioning

confidence: 99%

Effects of Melatonin on Liver Injuries and Diseases

Zhang

Meng

et al. 2017

IJMS

102

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Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.

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“…Hepatic fibrosis is the wound‐healing process in response to chronic liver injury . Hepatic stellate cell (HSC) constitutes the accumulation of extracellular matrix (ECM) once they activated . The activated HSC expresses a variety of factors such as transforming growth factor‐β1 (TGF‐β1), which stimulate the HSC activation, and secrete collagens and smooth muscle α‐action (α‐SMA) .…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

Yang

Zhang

et al. 2020

J Cellular Molecular Medi

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Long non‐coding RNAs (LncRNAs) and DNA methylation are important epigenetic mark play a key role in liver fibrosis. Currently, how DNA methylation and LncRNAs control the hepatic stellate cell (HSC) activation and fibrosis has not yet been fully characterized. Here, we explored the role of antisense non‐coding RNA in the INK4 locus (ANRIL) and DNA methylation in HSC activation and fibrosis. The expression levels of DNA methyltransferases 3A (DNMT3A), ANRIL, α‐Smooth muscle actin (α‐SMA), Type I collagen (Col1A1), adenosine monophosphate‐activated protein kinase (AMPK) and p‐AMPK in rat and human liver fibrosis were detected by immunohistochemistry, qRT‐PCR and Western blotting. Liver tissue histomorphology was examined by haematoxylin and eosin (H&E), Sirius red and Masson staining. HSC was transfected with DNMT3A‐siRNA, over‐expressing ANRIL and down‐regulating ANRIL. Moreover, cell proliferation ability was examined by CCK‐8, MTT and cell cycle assay. Here, our study demonstrated that ANRIL was significantly decreased in activated HSC and liver fibrosis tissues, while Col1A1, α‐SMA and DNMT3A were significantly increased in activated HSC and liver fibrosis tissues. Further, we found that down‐regulating DNMT3A expression leads to inhibition of HSC activation. Reduction in DNMT3A elevated ANRIL expression in activated HSC. Furthermore, we performed the over expression ANRIL suppresses HSC activation and AMPK signalling pathways. In sum, our study found that epigenetic DNMT3A silencing of ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway. Targeting epigenetic modulators DNMT3A and ANRIL, and offer a novel approach for liver fibrosis therapy.

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Melatonin suppresses activation of hepatic stellate cells through RORα‐mediated inhibition of 5‐lipoxygenase

Cited by 46 publications

References 58 publications

An ω-3-enriched diet alone does not attenuate CCl 4 -induced hepatic fibrosis

An ω-3-enriched diet alone does not attenuate CCl 4 -induced hepatic fibrosis

Effects of Melatonin on Liver Injuries and Diseases

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

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