Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice

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Tomasic , N , Kotarsky , H , Figueiredo , R D O , Hansson , E , Mörgelin , M , Tomasic , I , Kallijärvi , J , Elmer , E , Jauhiainen , M , Eklund , E A & Fellman , V 2020 , ' Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice ' , Biochimica et Biophysica Acta. Molecular Basis of Disease , vol. 1866 , no. 1 , 165573 . https://doi.org/10.1016/j.bbadis.2019.165573

Title: Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice
Author: Tomasic, Nikica; Kotarsky, Heike; Figueiredo, Rejane de Oliveira; Hansson, Eva; Mörgelin, Matthias; Tomasic, Ivan; Kallijärvi, Jukka; Elmer, Eskil; Jauhiainen, Matti; Eklund, Erik A.; Fellman, Vineta
Contributor organization: STEMM - Stem Cells and Metabolism Research Program
Faculty of Medicine
University of Helsinki
Research Programs Unit
Clinicum
HUS Children and Adolescents
University Management
Date: 2020-01-01
Language: eng
Number of pages: 11
Belongs to series: Biochimica et Biophysica Acta. Molecular Basis of Disease
ISSN: 0925-4439
DOI: https://doi.org/10.1016/j.bbadis.2019.165573
URI: http://hdl.handle.net/10138/323948
Abstract: Mice homozygous for the human GRACILE syndrome mutation (Bcs1l (c.A232G)) display decreased respiratory chain complex III activity, liver dysfunction, hypoglycemia, rapid loss of white adipose tissue and early death. To assess the underlying mechanism of the lipodystrophy in homozygous mice (Bcs1l(p.S)(78G)), these and wild-type control mice were subjected to a short 4-hour fast. The homozygotes had low baseline blood glucose values, but a similar decrease in response to fasting as in wild-type mice, resulting in hypoglycemia in the majority. Despite the already depleted glycogen and increased triacylglycerol content in the mutant livers, the mice responded to fasting by further depletion and increase, respectively. Increased plasma free fatty acids (FAs) upon fasting suggested normal capacity for mobilization of lipids from white adipose tissue into circulation. Strikingly, however, serum glycerol concentration was not increased concomitantly with free FM, suggesting its rapid uptake into the liver and utilization for fuel or gluconeogenesis in the mutants. The mutant hepatocyte mitochondria were capable of responding to fasting by appropriate morphological changes, as analyzed by electron microscopy, and by increasing respiration. Mutants showed increased hepatic gene expression of major metabolic controllers typically associated with fasting response (Ppargc1a, Fgf21, Cd36) already in the fed state, suggesting a chronic starvation-like metabolic condition. Despite this, the mutant mice responded largely normally to fasting by increasing hepatic respiration and switching to FA utilization, indicating that the mechanisms driving these adaptations are not compromised by the CIII dysfunction. Summary statement: Bcs1l mutant mice with severe CIII deficiency, energy deprivation and post-weaning lipolysis respond to fasting similarly to wild-type mice, suggesting largely normal systemic lipid mobilization and utilization mechanisms.
Subject: Mitochondrial disorder
Liver disease
OXPHOS
BCS1L
Fasting
Lipid metabolism
GLYCEROL-3-PHOSPHATE DEHYDROGENASE
LIPOPROTEIN-LIPASE
GRACILE SYNDROME
ACID-METABOLISM
IRON-OVERLOAD
MOUSE-LIVER
OXIDATION
KETOGENESIS
INCREASES
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: publishedVersion


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