Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis

Chen, Lixian; Zhou, Tianhao; Wu, Nan; O’Brien, April; Venter, Julie; Ceci, Ludovica; Kyritsi, Konstantina; Onori, Paolo; Gaudio, Eugenio; Sybenga, Amelia; Xie, Linglin; Wu, Chaodong; Fabris, Luca; Invernizzi, Pietro; Zawieja, David C.; Liangpunsakul, Suthat; Meng, Fanyin; Francis, Heather; Alpini, Gianfranco; Huang, Qiaobing; Glaser, Shannon

doi:10.1016/j.bbadis.2019.03.002

Cited by 23 publications

(61 citation statements)

References 43 publications

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“…In this model, both pinealectomy and light treatment decreased serum melatonin levels and AANAT expression in cholangiocytes compared to control BDL rats . Pinealectomy or light treatment exacerbated ductular reaction and liver fibrosis in BDL rats via elevated VEGF‐A and proinflammatory cytokine production, such as IL‐1β and IL‐6, as well as increased ROS levels in the liver . Mdr2 −/− mice are the most common mouse model for human PSC, which have similar conditions such as cholestasis, biliary inflammation, ductular reaction, and liver fibrosis .…”

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 84%

“…Dark therapy for BDL rats attenuated ductular reaction and liver fibrosis by decreasing cAMP levels in cholangiocytes . A previous study has performed pinealectomy surgery or light treatment, which maintains animals in complete light 24 hours for 1 week, for BDL rats . In this model, both pinealectomy and light treatment decreased serum melatonin levels and AANAT expression in cholangiocytes compared to control BDL rats .…”

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 97%

“…64 Pinealectomy or light treatment exacerbated ductular reaction and liver fibrosis in BDL rats via elevated VEGF-A and proinflammatory cytokine production, such as IL-1β and IL-6, as well as increased ROS levels in the liver. 64 Mdr2 −/− mice are the most common mouse model for human PSC, which have similar conditions such as cholestasis, biliary inflammation, ductular reaction, and liver fibrosis. 54 Dark therapy (complete dark for 1 week) or melatonin administration (2 mg/g body weight per day for 1 week via drinking water) for Mdr2 −/− mice improved liver conditions compared to control Mdr2 −/− mice with 12:12 hours light-dark cycle by inhibiting expression of VEGF-A/C in cholangiocytes via decreased levels of microRNA (miRNA) miR-200b.…”

Section: Cholangiopathiesmentioning

confidence: 98%

“…A previous study has performed pinealectomy surgery or light treatment, which maintains animals in complete light 24 hours for 1 week, for BDL rats . In this model, both pinealectomy and light treatment decreased serum melatonin levels and AANAT expression in cholangiocytes compared to control BDL rats . Pinealectomy or light treatment exacerbated ductular reaction and liver fibrosis in BDL rats via elevated VEGF‐A and proinflammatory cytokine production, such as IL‐1β and IL‐6, as well as increased ROS levels in the liver .…”

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 99%

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Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress‐induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.

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Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 84%

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 97%

Section: Cholangiopathiesmentioning

confidence: 98%

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 99%

See 2 more Smart Citations

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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“…Constant lighting is the extremity of prolonged light exposure. Constant or prolonged light exposure was reported to have a series of actions, such as brain development, psychosocial and emotional disorders, reproductive failure, biliary hyperplasia and liver fibrosis, increased oxidative stress and loss of circadian rhythms in locomotor activity, energy metabolism and insulin sensitivity (Tapia-Osorio et al, 2013;Alves-Simoes et al, 2016;Benedetto and Contin, 2019;Chen et al, 2019;Datta et al, 2019;Fobert et al, 2019;Haraguchi et al, 2019). The biological action of light on cardiovascular system is still unclear.…”

Section: Discussionmentioning

confidence: 99%

Constant Light Exerted Detrimental Cardiovascular Effects Through Sympathetic Hyperactivity in Normal and Heart Failure Rats

Jing¹,

Wu²,

et al. 2020

Front. Neurosci.

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It has been documented that constant light exposure exerts complicated cardiovascular effects. However, a mounting collection of conflicting results did not make it any easier for researchers and physicians to consider the role of light on cardiovascular function. This study was designed to investigate how constant light exposure (24 h light/day) influences the cardiac function in normal and heart-failure (HF) rats. In normal rats, two groups of SD rats were accustomed in 12 h light/12 h dark (LD) or 24 h light (constant light, CL) for 4 weeks. In HF rats which was induced by myocardial infarction (MI) was let recover in LD for 4 weeks. Interestingly, compared with rats in LD environment (ejection fraction, EF%: 93.64 ± 2.02 in LD, 14.62 ± 1.53 in HF-LD), constant light (2 weeks) weakened the cardiac function in normal and HF rats (EF%: 79.42 ± 2.91 in CL, 11.50 ± 1.08 in HF-CL). The levels of renal sympathetic nerve activity and c-fos expression in the rostral ventrolateral medulla (RVLM), a key region controlling sympathetic outflow, were significantly increased in normal and HF rats after

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The Apelin–Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis

et al. 2021

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Background and Aims Apelin (APLN) is the endogenous ligand of its G protein–coupled receptor, apelin receptor (APJ). APLN serum levels are increased in human liver diseases. We evaluated whether the APLN–APJ axis regulates ductular reaction and liver fibrosis during cholestasis. Approach and Results We measured the expression of APLN and APJ and serum APLN levels in human primary sclerosing cholangitis (PSC) samples. Following bile duct ligation (BDL) or sham surgery, male wild‐type (WT) mice were treated with ML221 (APJ antagonist) or saline for 1 week. WT and APLN−/− mice underwent BDL or sham surgery for 1 week. Multidrug resistance gene 2 knockout (Mdr2−/−) mice were treated with ML221 for 1 week. APLN levels were measured in serum and cholangiocyte supernatants, and cholangiocyte proliferation/senescence and liver inflammation, fibrosis, and angiogenesis were measured in liver tissues. The regulatory mechanisms of APLN–APJ in (1) biliary damage and liver fibrosis were examined in human intrahepatic biliary epithelial cells (HIBEpiCs) treated with APLN and (2) hepatic stellate cell (HSC) activation in APLN‐treated human HSC lines (HHSteCs). APLN serum levels and biliary expression of APLN and APJ increased in PSC samples. APLN levels were higher in serum and cholangiocyte supernatants from BDL and Mdr2−/− mice. ML221 treatment or APLN−/− reduced BDL‐induced and Mdr2−/−‐induced cholangiocyte proliferation/senescence, liver inflammation, fibrosis, and angiogenesis. In vitro, APLN induced HIBEpiC proliferation, increased nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expression, reactive oxygen species (ROS) generation, and extracellular signal–regulated kinase (ERK) phosphorylation. Pretreatment of HIBEpiCs with ML221, diphenyleneiodonium chloride (Nox4 inhibitor), N‐acetyl‐cysteine (NAC, ROS inhibitor), or PD98059 (ERK inhibitor) reduced APLN‐induced cholangiocyte proliferation. Activation of HHSteCs was induced by APLN but reduced by NAC. Conclusions The APLN–APJ axis induces cholangiocyte proliferation through Nox4/ROS/ERK‐dependent signaling and HSC activation through intracellular ROS. Modulation of the APLN–APJ axis may be important for managing cholangiopathies.

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Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis

Cited by 23 publications

References 43 publications

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Constant Light Exerted Detrimental Cardiovascular Effects Through Sympathetic Hyperactivity in Normal and Heart Failure Rats

The Apelin–Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis

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