Nonalcoholic fatty liver disease in CLOCK mutant mice

Pan, Xiaoyue; Queiroz, Joyce; Hussain, M. Mahmood

doi:10.1172/jci132765

Cited by 19 publications

(23 citation statements)

References 41 publications

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“…In the literature, variable and controversial results have been reported regarding the role of Bmal1 and Clock in the instauration of fibrosis. While a pro-fibrotic role of these proteins was observed in some studies in the context of kidney, lung and heart disease 29,33,36 , Bmal1 and Clock appear to exert a protective role in other studies related to kidney, lung and liver fibrosis 11,37–40 . In contrast, our observations in the CDKO mice are concordant with studies in other fibrotic contexts.…”

Section: Discussionmentioning

confidence: 97%

Cross regulation between the molecular clock and kidney inflammatory, metabolic and fibrotic responses

Rey-Serra

Tituaña

Lin

et al. 2022

Preprint

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Chronic kidney disease is a highly prevalent condition that remains a major clinical and biomedical challenge. Tubulo-interstitial fibrosis is the common pathological substrate for many causes that lead to chronic kidney disease. It is characterized by profound derangements in metabolic and inflammatory responses, whereby functional tissue is replaced with extracellular matrix, leading to the suppression of renal function. Perturbations in the circadian rhythm have been associated with many human pathologies, including renal disease. However, the role of the molecular clock in the instauration of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (UUO, FAN and adenine toxicity), employing genetically-modified mice with selective deficiencies of the clock components Bmal1, Clock and Cry. We found that UUO induced a marked increase in the expression of Bmal1. In human tubular epithelial cells, the pro-fibrotic mediator, TGF-beta, significantly altered the expression of core clock components. We further observed that the absence of Cry drastically aggravated kidney fibrosis, while both Cry and Clock played a role in the neutrophil and macrophage mediated inflammatory response, respectively. Suppression of Cry1/2 was associated with a major shift in the expression of metabolism-related genes, underscoring the importance of metabolic dysfunction in fibrosis. These results support a reciprocal interaction between the circadian clock and the response to kidney injury.

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Section: Discussionmentioning

confidence: 97%

Cross regulation between the molecular clock and kidney inflammatory, metabolic and fibrotic responses

Rey-Serra

Tituaña

Lin

et al. 2022

Preprint

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“…In CLOCK deficiency, HIF1α binds to the Cd36 promoter, promoting CD36 expression and uptake of fatty acids in the liver. This regulatory link among hypoxia, metabolism, and circadian locomotor promotes cirrhosis in NAFLD (Pan et al, 2020). Studies of high cholesterol diet (HCD)-induced liver fibrosis revealed that inducible nitric oxide synthase (iNOS)-mediated enhancement of fibrosis was associated with HIF1α stabilization (Anavi et al, 2015).…”

Section: Hif Mediated-metabolic Regulation In Liver Fibrosismentioning

confidence: 99%

Immune and Metabolic Alterations in Liver Fibrosis: A Disruption of Oxygen Homeostasis?

Zhang

Wang

et al. 2022

Front. Mol. Biosci.

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According to the WHO, “cirrhosis of the liver” was the 11th leading cause of death globally in 2019. Many kinds of liver diseases can develop into liver cirrhosis, and liver fibrosis is the main pathological presentation of different aetiologies, including toxic damage, viral infection, and metabolic and genetic diseases. It is characterized by excessive synthesis and decreased decomposition of extracellular matrix (ECM). Hepatocyte cell death, hepatic stellate cell (HSC) activation, and inflammation are crucial incidences of liver fibrosis. The process of fibrosis is also closely related to metabolic and immune disorders, which are usually induced by the destruction of oxygen homeostasis, including mitochondrial dysfunction, oxidative stress, and hypoxia pathway activation. Mitochondria are important organelles in energy generation and metabolism. Hypoxia-inducible factors (HIFs) are key factors activated when hypoxia occurs. Both are considered essential factors of liver fibrosis. In this review, the authors highlight the impact of oxygen imbalance on metabolism and immunity in liver fibrosis as well as potential novel targets for antifibrotic therapies.

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“…Clock gene whole-body mutant mice show increased susceptibility to several metabolic diseases, most of which are related to lipid metabolic disorders. For example, Clock mutant and Bmal1 –/– mice present hyperlipidemia and hepatic steatosis [ 57 , 58 , 59 ], while Per2 –/– mice show altered lipid metabolism [ 60 ]. Lastly, Rev-Erbα/β ablation leads to hepatic steatosis [ 61 ].…”

Section: Circadian Rhythms and Hepatic Metabolismmentioning

confidence: 99%

“…These studies are in agreement with published data in humans, in which comparing HCC samples to their corresponding adjacent normal tissue shows significant alterations in the circadian genes Per and Cry [ 92 , 93 , 94 ]. As mentioned above, mice with loss-of-function of the Clock gene spontaneously develop NAFLD in certain chow diet conditions (such as HFD), which can progress to steatohepatitis and cirrhosis with age [ 58 ]. The additional deletion of the apolipoprotein ApoE, whose deficiency increases the susceptibility to NALFD under HFD conditions, increases the liver pathology in these mice, including the augmented expression of cancer markers in the liver [ 58 ].…”

Section: Role Of Circadian Rhythms In Liver Cancermentioning

confidence: 99%

“…As mentioned above, mice with loss-of-function of the Clock gene spontaneously develop NAFLD in certain chow diet conditions (such as HFD), which can progress to steatohepatitis and cirrhosis with age [ 58 ]. The additional deletion of the apolipoprotein ApoE, whose deficiency increases the susceptibility to NALFD under HFD conditions, increases the liver pathology in these mice, including the augmented expression of cancer markers in the liver [ 58 ]. Analysis of miRNA profiles in liver from Clock mutant mice revealed that Clock-regulated miRNAs may be involved in cancer initiation or progression by controlling genes related to cell proliferation, invasion and/or metabolism in the mouse liver [ 95 ].…”

Section: Role Of Circadian Rhythms In Liver Cancermentioning

confidence: 99%

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Circadian Clock and Liver Cancer

Crespo

Leiva

Sabio

2021

Cancers

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Circadian clocks control several homeostatic processes in mammals through internal molecular mechanisms. Chronic perturbation of circadian rhythms is associated with metabolic diseases and increased cancer risk, including liver cancer. The hepatic physiology follows a daily rhythm, driven by clock genes that control the expression of several proteins involved in distinct metabolic pathways. Alteration of the liver clock results in metabolic disorders, such as non-alcoholic fatty liver diseases (NAFLD) and impaired glucose metabolism, that can trigger the activation of oncogenic pathways, inducing spontaneous hepatocarcinoma (HCC). In this review, we provide an overview of the role of the liver clock in the metabolic and oncogenic changes that lead to HCC and discuss new potentially useful targets for prevention and management of HCC.

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Nonalcoholic fatty liver disease in CLOCK mutant mice

Cited by 19 publications

References 41 publications

Cross regulation between the molecular clock and kidney inflammatory, metabolic and fibrotic responses

Cross regulation between the molecular clock and kidney inflammatory, metabolic and fibrotic responses

Immune and Metabolic Alterations in Liver Fibrosis: A Disruption of Oxygen Homeostasis?

Circadian Clock and Liver Cancer

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