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Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice
Lund Univ, Dept Clin Sci, Pediat, Klin Gatan 12, S-22184 Lund, Sweden.;Karolinska Univ Hosp, Dept Neonatol, Stockholm, Sweden.;Univ Zagreb, Dept Biol, Fac Sci, Zagreb, Croatia..
Lund Univ, Dept Pathol, Lund, Region Skane, Sweden..
Folkhalsan Res Ctr, Helsinki, Finland..
Lund Univ, Dept Clin Sci, Pediat, Klin Gatan 12, S-22184 Lund, Sweden..
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2020 (English)In: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1866, no 1, article id 165573Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Amsterdam: ELSEVIER , 2020. Vol. 1866, no 1, article id 165573
Keywords [en]
Mitochondrial disorder, Liver disease, OXPHOS, BCS1L, Fasting, Lipid metabolism
National Category
Physiology Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:mdh:diva-46596DOI: 10.1016/j.bbadis.2019.165573ISI: 000500361800007PubMedID: 31672551Scopus ID: 2-s2.0-85074150516OAI: oai:DiVA.org:mdh-46596DiVA, id: diva2:1381096
Available from: 2019-12-20 Created: 2019-12-20 Last updated: 2020-02-20Bibliographically approved

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Tomasic, Ivan

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