Tomasic 2019 Biochim Biophys Acta Mol Basis Dis
|Tomašić N, Kotarsky H, de Oliveira Figueiredo R, Hansson E, Mörgelin M, Tomašić I, Kallijärvi J, Elmér E, Jauhiainen M, Eklund EA, Fellman V (2019) Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice. Biochim Biophys Acta Mol Basis Dis 1866:165573.|
Tomasic N, Kotarsky H, de Oliveira Figueiredo R, Hansson E, Moergelin M, Tomasic I, Kallijaervi J, Elmer E, Jauhiainen M, Eklund EA, Fellman V (2019) Biochim Biophys Acta Mol Basis Dis
Abstract: Mice homozygous for the human GRACILE syndrome mutation (Bcs1lc.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 (Bcs1lp.S78G), 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 FAs, 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.
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.
Copyright © 2019. Published by Elsevier B.V. • Keywords: BCS1L, Fasting, Lipid metabolism, Liver disease, Mitochondrial disorder, OXPHOS • Bioblast editor: Plangger M • O2k-Network Lab: FI Helsinki Mervaala E, SE Lund Elmer E
Labels: MiParea: Respiration, nDNA;cell genetics, Exercise physiology;nutrition;life style
Organism: Mouse Tissue;cell: Liver Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, NS HRR: Oxygraph-2k