Dataset Information

Cavin1 Deficiency Causes Disorder of Hepatic Glycogen Metabolism and Neonatal Death by Impacting Fenestrations in Liver Sinusoidal Endothelial Cells.

ABSTRACT: It has been reported that Cavin1 deficiency causes lipodystrophy in both humans and mice by affecting lipid metabolism. The ablation of Cavin1 in rodents also causes a significant deviation from Mendelian ratio at weaning in a background-dependent manner, suggesting the presence of undiscovered functions of Cavin1. In the current study, the results show that Cavin1 deficiency causes neonatal death in C57BL/6J mice by dampening the storage and mobilization of glycogen in the liver, which leads to lethal neonatal hypoglycemia. Further investigation by electron microscopy reveals that Cavin1 deficiency impairs the fenestration in liver sinusoidal endothelial cells (LSECs) and impacts the permeability of endothelial barrier in the liver. Mechanistically, Cavin1 deficiency inhibits the RhoA-Rho-associated protein kinase 2-LIM domain kinase-Cofilin signaling pathway and suppresses the dynamics of the cytoskeleton, and eventually causes the reduction of fenestrae in LSECs. In addition, the defect of fenestration in LSECs caused by Cavin1 deficiency can be rescued by treatment with the F-actin depolymerization reagent latrunculin A. In summary, the current study reveals a novel function of Cavin1 on fenestrae formation in LSECs and liver glycogen metabolism, which provide an explanation for the neonatal death of Cavin1 null mice and a potential mechanism for metabolic disorders in patients with Cavin1 mutation.

SUBMITTER: Wei Z

PROVIDER: S-EPMC7539207 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Cavin1 Deficiency Causes Disorder of Hepatic Glycogen Metabolism and Neonatal Death by Impacting Fenestrations in Liver Sinusoidal Endothelial Cells.

Wei Zhuang Z Lei Jigang J Shen Feng F Dai Yuxiang Y Sun Yan Y Liu Yilian Y Dai Yan Y Jian Zhijie Z Wang Shilong S Chen Zhengjun Z Liao Kan K Hong Shangyu S

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200821 19

It has been reported that Cavin1 deficiency causes lipodystrophy in both humans and mice by affecting lipid metabolism. The ablation of Cavin1 in rodents also causes a significant deviation from Mendelian ratio at weaning in a background-dependent manner, suggesting the presence of undiscovered functions of Cavin1. In the current study, the results show that Cavin1 deficiency causes neonatal death in C57BL/6J mice by dampening the storage and mobilization of glycogen in the liver, which leads to ...[more]

PMID: 33042738

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Project description:BackgroundOver one million babies are stillborn or die within the first 28 days of life each year due to preventable causes and poor-quality care in resource-constrained countries. Death audit may be a valuable tool for improving quality of care and decreasing mortality. However, challenges in implementing audit and their subsequent action plans have been reported, with few successfully implemented and sustained. This study aimed to identify factors that affect stillbirth and neonatal death audit at the facility level in the southern region of Malawi.MethodsThirty-eight semi-structured interviews and seven focus group discussions with death audit committee members were conducted. Thematic analysis was guided by a conceptual framework applied deductively, combined with inductive line-by-line coding to identify additional emerging themes.ResultsThe factors that affected audit at individual, facility and national level were related to training, staff motivation, power dynamics and autonomy, audit organisation and data support. We found that factors were linked because they informed each other. Inadequate staff training was caused by a lack of financial allocation at the facility level and donor-driven approaches to training at the national level, with training taking place only with support from funders. Staff motivation was affected by the institutional norms of reliance on monetary incentives during meetings, gazetted at the national level so that audits happened only if such incentives were available. This overshadowed other benefits and non-monetary incentives which were not promoted at the facility level. Inadequate resources to support audit were informed by limited facility-level autonomy and decision-making powers which remained controlled at the national level despite decentralisation. Action plan implementation challenges after audit meetings resulted from inadequate support at the facility level and inadequate audit policy and guidelines at the national level. Poor documentation affected audit processes informed by inadequate supervision and promotion of data usage at both facility and national levels.ConclusionsGiven that the factors that facilitate or inhibit audits are interconnected, implementers, policymakers and managers need to be aware that addressing barriers is likely to require a whole health systems approach targeting all system levels. This will require behavioural and complex intervention approaches.

Dataset Information

Cavin1 Deficiency Causes Disorder of Hepatic Glycogen Metabolism and Neonatal Death by Impacting Fenestrations in Liver Sinusoidal Endothelial Cells.

Publications

Cavin1 Deficiency Causes Disorder of Hepatic Glycogen Metabolism and Neonatal Death by Impacting Fenestrations in Liver Sinusoidal Endothelial Cells.

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