Deletion of clock gene Per2 exacerbates cholestatic liver injury and fibrosis in mice

Chen, Peng; Kakan, Xiamusiya; Wang, Shiming; Dong, Wei; Jia, Ai‐Qun; Cai, Chun; Zhang, Jianfa

doi:10.1016/j.etp.2011.12.007

Cited by 34 publications

(32 citation statements)

References 23 publications

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“…Our present study shows decreased expression of Per1, BMAL1, CLOCK, and Cry1 and supports the concept that clock genes play a key role in the modulation of liver injury (15)(16)(17). For example, the expression of fibrosis-related genes such as TGF-␤, COLA1, and TIMP1 is elevated in cholestatic Per2 knockout mice, suggesting that the clock gene Per2 plays a protective role in during liver injury (16). Also, the loss of the clock gene, mPer2, has been shown to promote liver fibrosis induced by carbon tetrachloride (15).…”

Section: Discussionsupporting

confidence: 91%

Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis

Han

Onori

Meng³

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Biliary hyperplasia and liver fibrosis are common features in cholestatic liver disease. Melatonin is synthesized by the pineal gland as well as the liver. Melatonin inhibits biliary hyperplasia of bile duct-ligated (BDL) rats. Since melatonin synthesis (by the enzyme serotonin N-acetyltransferase, AANAT) from the pineal gland increases after dark exposure, we hypothesized that biliary hyperplasia and liver fibrosis are diminished by continuous darkness via increased melatonin synthesis from the pineal gland. Normal or BDL rats (immediately after surgery) were housed with light-dark cycles or complete dark for 1 wk before evaluation of 1) the expression of AANAT in the pineal gland and melatonin levels in pineal gland tissue supernatants and serum; 2) biliary proliferation and intrahepatic bile duct mass, liver histology, and serum chemistry; 3) secretin-stimulated ductal secretion (functional index of biliary growth); 4) collagen deposition, liver fibrosis markers in liver sections, total liver, and cholangiocytes; and 5) expression of clock genes in cholangiocytes. In BDL rats exposed to dark there was 1) enhanced AANAT expression/melatonin secretion in pineal gland and melatonin serum levels; 2) improved liver morphology, serum chemistry and decreased biliary proliferation and secretin-stimulated choleresis; and 4) decreased fibrosis and expression of fibrosis markers in liver sections, total liver and cholangiocytes and reduced biliary expression of the clock genes PER1, BMAL1, CLOCK, and Cry1. Thus prolonged dark exposure may be a beneficial noninvasive therapeutic approach for the management of biliary disorders.

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Section: Discussionsupporting

confidence: 91%

Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis

Han

Onori

Meng³

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…During the initiation of carcinogenesis, NF-κB overexpression accelerates cellular proliferation and inhibits apoptosis through the activation of IL-6 and TNF-α genes [33, 34]. Indeed, Per2 -/- mice, a construct which differed from Per2 m/m by the lack of any PER2 protein, also displayed increased TNF-α expression jointly with liver cholestasis or fibrosis, in response to physical liver injury [35]. …”

Section: Discussionmentioning

confidence: 99%

Clock gene Per2 as a controller of liver carcinogenesis

et al. 2016

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Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression.

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“…In contrast, Per1 and Per2, which provide negative feedback by interfering with the Npas/Bmal1/Clock transcriptional complexes, are down-regulated, and Cry1 was unchanged. In the bile duct ligation model of Per2-null mice Per2 played a protective effects of cholestasis, atorvastatin repressed the expression of this feedback genes may increase the risk of Liver injury (Chen et al, 2013). Thus, atorvastatin-induced disruption of hepatic BA homeostasis was related to the core-clock gene alterations.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice

et al. 2017

PeerJ

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AimAtorvastatin is a HMG-CoA reductase inhibitor used for hyperlipidemia. Atorvastatin is generally safe but may induce cholestasis. The present study aimed to examine the effects of atorvastatin on hepatic gene expression related to bile acid metabolism and homeostasis, as well as the expression of circadian clock genes in livers of mice.MethodsAdult male mice were given atorvastatin (10, 30, and 100 mg/kg, po) daily for 30 days, and blood biochemistry, histopathology, and gene expression were examined.ResultsRepeated administration of atorvastatin did not affect animal body weight gain or liver weights. Serum enzyme activities were in the normal range. Histologically, the high dose of atorvastatin produced scattered swollen hepatocytes, foci of feathery-like degeneration, together with increased expression of Egr-1 and metallothionein-1. Atorvastatin increased the expression of Cyp7a1 in the liver, along with FXR and SHP. In contract, atorvastatin decreased the expression of bile acid transporters Ntcp, Bsep, Ostα, and Ostβ. The most dramatic change was the 30-fold induction of Cyp7a1. Because Cyp7a1 is a circadian clock-controlled gene, we further examined the effect of atorvastatin on clock gene expression. Atorvastatin increased the expression of clock core master genes Bmal1 and Npas2, decreased the expression of clock feedback genes Per2, Per3, and the clock targeted genes Dbp and Tef, whereas it had no effect on Cry1 and Nr1d1 expression.ConclusionRepeated administration of atorvastatin affects bile acid metabolism and markedly increases the expression of the bile acid synthesis rate-limiting enzyme gene Cyp7a1, together with alterations in the expression of circadian clock genes.

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Deletion of clock gene Per2 exacerbates cholestatic liver injury and fibrosis in mice

Cited by 34 publications

References 23 publications

Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis

Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis

Clock gene Per2 as a controller of liver carcinogenesis

Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice

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