Cell cycle regulation in NAFLD: when imbalanced metabolism limits cell division

Caldez, Matias J.; Björklund, Mikael; Kaldis, Philipp

doi:10.1007/s12072-020-10066-6

Cited by 41 publications

(39 citation statements)

References 97 publications

(153 reference statements)

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“…This was most noticeable in the direct upregulation of the G s G-protein (GNAS) by RIS, and the direct downregulation of the G i G-protein (GNAI1) by OLAN, both of which were featured in numerous KEGG pathway maps. Globally impaired metabolic pathways, especially deficient production of amino acids, nucleic acids, and ATP, also limit the mitigation of NAFLD by inhibiting cell replication and repair mechanisms [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

Rostama

Beauchemin

Bouchard

et al. 2020

IJMS

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Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls (p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology.

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Section: Discussionmentioning

confidence: 99%

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

Rostama

Beauchemin

Bouchard

et al. 2020

IJMS

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“…A remarkable feature of the liver is its ability to regenerate after injury or resection. Many studies focus on the regulation of the cell cycle or metabolic processes that promote the regenerative response of the liver to partial hepatectomy (PH) [85,86]. Here, we identified the novel involvement of Atf6 and CPATs during liver regeneration after PH in wild type mouse livers.…”

Section: Discussionmentioning

confidence: 99%

Permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver

Nair

Lakhiani

Zhang

et al. 2021

Preprint

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Proteostatic stress initiates a transcriptional response that is unique to the stress condition, yet the regulatory mechanisms underlying the distinct gene expression patterns observed in stressed cells remains unknown. Using a functional genomic approach, we investigated how activating transcription factor 6 (ATF6), a key transcription factor in the unfolded protein response (UPR), regulates target genes. We first designed a computational strategy to define Atf6 target genes based on the evolutionary conservation of predicted ATF6 binding in gene promoters, identifying 652 conserved putative Atf6 target (CPAT) genes. CPATs were overrepresented for genes functioning in the UPR, however, the majority functioned in cellular processes unrelated to proteostasis, including small molecule metabolism and development. Functional studies of stress-independent and toxicant based Atf6 activation in zebrafish livers showed that the pattern of CPAT expression in response to Atf6 overexpression, alcohol and arsenic was unique. Only 34 CPATs were differentially expressed in all conditions, indicating that Atf6 is sufficient to regulate a small subset of CPATs. Blocking Atf6 using Ceapins in zebrafish demonstrated that Atf6 is necessary for activation of these genes in response to arsenic. We investigated CPAT during physiologically mediated hepatocyte stress using liver regeneration in mice as a model. Over half of all CPATs were differentially expressed during this process. This was attributed to the permissive chromatin environment in quiescent livers on the promoters of these genes, characterized by the absence of H3K27me3 and enrichment of H3K4me3. Taken together, these data uncover a complex transcriptional response to Atf6 activation and implicate a permissive epigenome as a mechanism by which distinct transcriptional responses are regulated by Atf6.

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“…However, for some tissues, this idea does not hold true. For example, even when hepatocyte proliferation is inhibited after hepatectomy, liver regeneration is compensated by the mechanism of cellular hypertrophy ( Caldez et al, 2018 , 2020 ). Interestingly, in bone tissue, parathyroid hormone treatment reverses bone loss after ovariectomy even when osteoblasts cannot proliferate ( Takahashi et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase 1 Is Essential for Muscle Regeneration and Overload Muscle Fiber Hypertrophy

Kobayashi

Tanaka

Mulati

et al. 2020

Front. Cell Dev. Biol.

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Satellite cell proliferation is an essential step in proper skeletal muscle development and muscle regeneration. However, the mechanisms regulating satellite cell proliferation are relatively unknown compared to the knowledge associated with the differentiation of satellite cells. Moreover, it is still unclear whether overload muscle fiber hypertrophy is dependent on satellite cell proliferation. In general, cell proliferation is regulated by the activity of cell cycle regulators, such as cyclins and cyclin-dependent kinases (CDKs). Despite recent reports on the function of CDKs and CDK inhibitors in satellite cells, the physiological role of Cdk1 in satellite cell proliferation remains unknown. Herein, we demonstrate that Cdk1 regulates satellite cell proliferation, muscle regeneration, and muscle fiber hypertrophy. Cdk1 is highly expressed in myoblasts and is downregulated upon myoblast differentiation. Inhibition of CDK1 activity inhibits myoblast proliferation. Deletion of Cdk1 in satellite cells leads to inhibition of muscle recovery after muscle injury due to reduced satellite cell proliferation in vivo . Finally, we provide direct evidence that Cdk1 expression in satellite cells is essential for overload muscle fiber hypertrophy in vivo . Collectively, our results demonstrate that Cdk1 is essential for myoblast proliferation, muscle regeneration, and muscle fiber hypertrophy. These findings could help to develop treatments for refractory muscle injuries and muscle atrophy, such as sarcopenia.

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Cell cycle regulation in NAFLD: when imbalanced metabolism limits cell division

Cited by 41 publications

References 97 publications

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

Permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver

Cyclin-Dependent Kinase 1 Is Essential for Muscle Regeneration and Overload Muscle Fiber Hypertrophy

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