Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

Ji, Shaonin; You, Yun; Kerner, János; Hoppel, Charles L.; Schoeb, Trenton R.; Chick, Wallace S.; Hamm, Doug A.; Sharer, J. Daniel; Wood, Philip A.

doi:10.1016/j.ymgme.2007.10.006

Cited by 88 publications

(69 citation statements)

References 40 publications

(61 reference statements)

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“…Our findings provide support for the notion that the TRL-mediated delivery of fatty acid fuel to BAT is important for thermogenesis. It is now clear that defective intravascular lipolysis (e.g., GPIHBP1 deficiency), defective entry of fatty acids into mitochondria (e.g., CPT-1 deficiency) (38), defects in intracellular fatty acid trafficking (e.g., FABP3…”

Section: Discussionmentioning

confidence: 99%

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Larsson

Allan

Heizer

et al. 2018

Journal of Lipid Research

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Glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1), an endothelial cell protein, binds LPL in the subendothelial spaces and transports it to the capillary lumen. In Gpihbp1−/− mice, LPL remains stranded in the subendothelial spaces, causing hypertriglyceridemia, but how Gpihbp1−/− mice respond to metabolic stress (e.g., cold exposure) has never been studied. In wild-type mice, cold exposure increases LPL-mediated processing of triglyceride-rich lipoproteins (TRLs) in brown adipose tissue (BAT), providing fuel for thermogenesis and leading to lower plasma triglyceride levels. We suspected that defective TRL processing in Gpihbp1−/− mice might impair thermogenesis and blunt the fall in plasma triglyceride levels. Indeed, Gpihbp1−/− mice exhibited cold intolerance, but the effects on plasma triglyceride levels were paradoxical. Rather than falling, the plasma triglyceride levels increased sharply (from ∼4,000 to ∼15,000 mg/dl), likely because fatty acid release by peripheral tissues drives hepatic production of TRLs that cannot be processed. We predicted that the sharp increase in plasma triglyceride levels would not occur in Gpihbp1−/−Angptl4−/− mice, where LPL activity is higher and baseline plasma triglyceride levels are lower. Indeed, the plasma triglyceride levels in Gpihbp1−/−Angptl4−/− mice fell during cold exposure. Metabolic studies revealed increased levels of TRL processing in the BAT of Gpihbp1−/−Angptl4−/− mice.

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Section: Discussionmentioning

confidence: 99%

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Larsson

Allan

Heizer

et al. 2018

Journal of Lipid Research

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“…Concomitantly, the expression of Fabp3 and Cpt1b is elevated. Both proteins have been shown to deliver FFA to mitochondrial ␤-oxidation in BAT (37,38).…”

Section: Discussionmentioning

confidence: 99%

NAT8L (N-Acetyltransferase 8-Like) Accelerates Lipid Turnover and Increases Energy Expenditure in Brown Adipocytes

Pessentheiner

Pelzmann

Walenta

et al. 2013

Journal of Biological Chemistry

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Background: NAT8L (N-acetyltransferase 8-like) synthesizes N-acetylaspartate and is required for myelination in the brain. Its function in other tissues was undefined. Results: Nat8l is highly expressed in adipose tissues and impacts adipogenic marker gene expression, lipid turnover, and energy metabolism in brown adipocytes. Conclusion: Nat8l expression influences cellular bioenergetics in adipocytes. Significance: These findings establish a novel pathway in brown adipocyte metabolism.

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“…It is generally thought that circulating fatty acids are not readily oxidized by fetal tissue (28), although mice null for enzymes in the rate-setting step of mitochondrial ␤-oxidation of long-chain fatty acids (Cpt1a and Cpt1b) exhibit embryonic lethality before e10 (29,30). The extent to which fatty acids and other lipids are able to cross the placenta and contribute to lipid accumulation in the fetus is also debated and varies from species to species (31,32).…”

Section: Mpc Deficiency Promotes Metabolic Plasticity In Uteromentioning

confidence: 99%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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bGlucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. E mbryonic development in eutherian mammals is defined by ongoing metabolic interactions between mother and fetus. Placentas have evolved a sophisticated suite of adaptations to ensure adequate nutrient, gas, and waste exchange between fetus and mother, as well as hormonal and immunological communication (1, 2). To meet the fetal requirements for nutrient and oxygen consumption during pregnancy, maternal cardiac output increases such that uteroplacental blood flow accounts for ϳ25% of total cardiac output (3). Glucose and oxygen are arguably the two most important molecules transferred from mother to fetus, in terms of both concentration and the multitude of physiological adaptations in place to ensure their adequate transport; however, the requirement for mitochondrial oxidative metabolism during embryonic development remains poorly defined.While oxygen tension in utero is low relative to atmospheric levels, measurement of oxygen consumption and lactate uptake in fetal lambs provided evidence that the fetus is a net consumer rather than a producer of lactate (4). Consistent with this, fetal myocardium consumes a large amount of lactate, in addition to glucose, indicating that oxidative metabolism of carbohydrates is an important energy source in the developing heart (5, 6). Additionally, lactate utilization is high in the neonatal brain, and the capacity for lactate import is higher in the neonatal brain than in the adult brain (7). Together, these observations provide evidence for the importance of mitochondrial oxidative metabolism early in mammalian development. S...

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Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

Cited by 88 publications

References 40 publications

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

NAT8L (N-Acetyltransferase 8-Like) Accelerates Lipid Turnover and Increases Energy Expenditure in Brown Adipocytes

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

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