Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation

Kurtz, David M.; Rinaldo, Piero; Rhead, William J.; Tian, Liqun; Millington, David S.; Vockley, Jerry; Hamm, Doug A.; Brix, Amy E.; Lindsey, J. Russell; Pinkert, Carl A.; O’Brien, William E.; Wood, Philip A.

doi:10.1073/pnas.95.26.15592

Cited by 216 publications

(212 citation statements)

References 30 publications

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“…This is because deficiency in FAO not only reduces fat-derived energy supply but also leads to accumulation of fatty acid substrates or metabolites in the blood and other extra-cellular fluid compartment, in cytoplasm, and in mitochondria. Because CPT-1 is the rate-limiting enzyme for mitochondrial LCFA β-oxidation important in gametogenesis and embryogenesis [29][30][31], it is not surprising that, among available mouse models with enzyme deficiencies of FAO, a severe phenotype, or homozygous lethality is found in mice deficient in either CPT-1a [10] or CPT-1b (this study), in contrast to those with homozygous deficiency of any one of the four fatty acyl-CoA dehydrogenases (ACADs), which include very-long-, long-, medium-, and short-chain acyl-CoA dehydrogenases (VLCAD [32]; LCAD [33], MCAD [34]; and SCAD [35,36]). Also, among the four mouse models with deficiency in one of the ACADs, LCAD−/ − mice have the most severe phenotype including fatty liver, fasting and cold intolerance and gestational loss [33].…”

Section: Discussionmentioning

confidence: 92%

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

You

Kerner

et al. 2008

Molecular Genetics and Metabolism

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Carnitine palmitoyltransferase-1 (CPT-1) catalyzes the rate-limiting step of mitochondrial β-oxidation of long chain fatty acids (LCFA), the most abundant fatty acids in mammalian membranes and in energy metabolism. Human deficiency of the muscle isoform CPT-1b is poorly understood. In the current study, embryos with a homozygous knockout of Cpt-1b were lost before embryonic day 9.5 − 11.5. Also, while there were normal percentages of CPT-1b+/−pups born from both male and female CPT-1b+/− mice crossed with wild-type mates, the number of CPT-1b+/− pups from CPT-1b+/− breeding pairs was under-represented (63% of the expected number). Northern blot analysis demonstrated ∼50% Cpt-1b mRNA expression in brown adipose tissue (BAT), heart and skeletal muscles in the CPT-1b+/− male mice. Consistent with tissue-specific expression of Cpt-1b mRNA in muscle but not liver, CPT-1+/− mice had ∼60% CPT-1 activity in skeletal muscle and no change in total liver CPT-1 activity. CPT-1b+/− mice had normal fasting blood glucose concentration. Consistent with expression of CPT-1b in BAT and muscle, ∼7% CPT-1b+/− mice (n=30) developed fatal hypothermia following a 3 hr cold challenge, while none of the CPT-1b+/+ mice (n=30) did. With a prolonged cold challenge (6 hr), significantly more CPT-1b+/− mice developed fatal hypothermia (52% CPT-1b+/− mice vs. 21% CPT-1b+/+ mice), with increased frequency in females of both genotypes (67% female vs. 38% male CPT-1b+/− mice, and 33% female vs. 8% male CPT-1b+/+ mice). Therefore, lethality of homozygous CPT-1b deficiency in the mice is consistent with paucity of human cases.

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Section: Discussionmentioning

confidence: 92%

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

You

Kerner

et al. 2008

Molecular Genetics and Metabolism

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“…This notion is supported by other genetic models of altered mitochondrial energy metabolism. For example, ablation of ␤-oxidation enzymes leads to hypoglycemia during fasting (33,34), whereas children with inborn errors in mitochondrial FAO or OXPHOS often present with hypoglycemia secondary to defects in gluconeogenesis (35)(36)(37)). The precise lesion (i.e.…”

Section: Discussionmentioning

confidence: 99%

Diminished Hepatic Gluconeogenesis via Defects in Tricarboxylic Acid Cycle Flux in Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α)-deficient Mice

Burgess

Leone

Wende

et al. 2006

Journal of Biological Chemistry

100

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The peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) is a highly inducible transcriptional coactivator implicated in the coordinate regulation of genes encoding enzymes involved in hepatic fatty acid oxidation, oxidative phosphorylation, and gluconeogenesis. The present study sought to assess the effects of chronic PGC-1␣ deficiency on metabolic flux through the hepatic gluconeogenic, fatty acid oxidation, and tricarboxylic acid cycle pathways. To this end, hepatic metabolism was assessed in wild-type (WT) and PGC-1␣ ؊/؊ mice using isotopomer-based NMR with complementary gene expression analyses. Hepatic glucose production was diminished in PGC-1␣ ؊/؊ livers coincident with reduced gluconeogenic flux from phosphoenolpyruvate. Surprisingly, the expression of PGC-1␣ target genes involved in gluconeogenesis was unaltered in PGC-1␣ ؊/؊ compared with WT mice under fed and fasted conditions. Flux through tricarboxylic acid cycle and mitochondrial fatty acid ␤-oxidation pathways was also diminished in PGC-1␣ ؊/؊ livers. The expression of multiple genes encoding tricarboxylic acid cycle and oxidative phosphorylation enzymes was significantly depressed in PGC-1␣ ؊/؊ mice and was activated by PGC-1␣ overexpression in the livers of WT mice. Collectively, these findings suggest that chronic wholeanimal PGC-1␣ deficiency results in defects in hepatic glucose production that are secondary to diminished fatty acid ␤-oxidation and tricarboxylic acid cycle flux rather than abnormalities in gluconeogenic enzyme gene expression per se.Flux through hepatic gluconeogenesis, fatty acid oxidation (FAO), 3 tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation (OXPHOS) pathways can be modulated at multiple regulatory levels. Substrate availability, post-translational modification, and transcriptional regulation of genes encoding enzymes at various points can influence the capacity for, and the rate of flux through, each of these pathways. Moreover, flux through one pathway has an inevitable impact on the flux of the others. For instance, mitochondrial FAO is the principal source of energy in the hepatocyte, impacting the amount of chemical work that can be performed by the liver. Furthermore, the tricarboxylic acid cycle not only oxidizes acetyl-CoA generated by ␤-oxidation and produces reducing equivalents for ATP synthesis but also supplies carbons necessary for gluconeogenesis through pyruvate carboxylase (PC) and P-enolpyruvate carboxykinase (PEPCK). Thus, the tricarboxylic acid cycle is a critical hub linking FAO with gluconeogenesis and OXPHOS pathways.Recent work has shown that the peroxisome proliferatoractivated receptor ␥ (PPAR␥) coactivator-1␣ (PGC-1␣) is a highly inducible transcriptional coactivator that integrates multiple interconnected metabolic pathways in liver (1). PGC-1␣ controls transcription of genes involved in hepatic gluconeogenesis, fatty acid catabolism, oxidative phosphorylation (OXPHOS), and mitochondrial biogenesis (1-3). Although PGC-1␣ was originally identified ...

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“…Mice deficient in the mitochondrial trifunctional protein crucial for ␤ oxidation died soon after birth as a result of cardiac lesions (50). Mice lacking the enzyme of FA oxidation long-chain acyl-CoA dehydrogenase appeared normal, but hypoglycemia and cardiac and hepatic lipidosis were noted with fasting, and sudden death was observed in Ϸ5% of the cases (51). The CD36-deficient mice have impaired FA oxidation that is secondary to a defect in membrane FA uptake.…”

Section: Discussionmentioning

confidence: 99%

Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

Irie

Krukenkamp

Brinkmann

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Long-chain fatty acid uptake, which provides a large part of myocardial energy, is impaired in human and murine hearts deficient in the membrane fatty acid translocase, FAT͞CD36. We examined myocardial function in CD36-null mice using the working heart. Fatty acid oxidation and stores of glycogen, triglycerides, and ATP were reduced in CD36-deficient hearts and were restored to WT levels by rescue of myocyte CD36. Under normal perfusion conditions, CD36-null hearts had similar cardiac outputs and end-diastolic pressures as WT or transgenic hearts. After 6 min of ischemia, cardiac output decreased by 41% and end diastolic pressure tripled for CD36-null hearts, with no significant changes in WT or transgenic hearts. Null hearts also failed more frequently after ischemia as compared with WT or transgenics. To dissect out contribution of fatty acid uptake, a perfusate-lacking fatty acids was used. This decreased cardiac output after ischemia by 30% in WT hearts as compared with 50% for CD36-deficient hearts. End diastolic pressure, a negative index of myocardial performance, increased after ischemia in all heart types. Addition to the perfusate of a medium-chain fatty acid (caprylic acid) that does not require CD36 for uptake alleviated poor ischemic tolerance of CD36-null hearts. In summary, recovery from ischemia is compromised in CD36-deficient hearts and can be restored by CD36 rescue or by supplying medium-chain fatty acids. It would be important to determine whether the findings apply to the human situation where polymorphisms of the CD36 gene are relatively common.CD36 rescue ͉ working heart ͉ fatty acid oxidation F atty acid (FA) uptake consists of two components, passive diffusion and carrier-mediated transport specific for FA with Ͼ8-10 carbons (1). An 88-kDa glycoprotein, FAT (2), a homolog of human CD36 (3, 4) was implicated in FA transport by labeling with the transport inhibitor sulfo-N-succinimidyl oleate (1, 5). The role of FAT͞CD36 in FA uptake was confirmed by studies of mice with CD36 deficiency or overexpression (6, 7). CD36 is abundant in the heart (2, 8), and its deficiency is associated with a 60-80% decrease in myocardial FA uptake (9, 10) and with a severalfold compensatory increase in glucose utilization (11).There is strong evidence for a critical role of CD36-facilitated FA uptake during muscle contraction, which was shown to recruit the protein to the plasma membrane (12). Muscle-targeted overexpression of CD36 enhanced FA oxidation in response to contraction severalfold (7). In line with this, CD36-null mice (6) perform poorly on treadmill and swimming tests (A.I., unpublished observations). However the impact of CD36 deficiency on the performance of the heart, which relies on FA for energy, remains unknown. Such information may have clinical relevance because incidence of CD36 deficiency in humans ranges between 0.3% and 18.5% depending on the population (13). CD36-deficient humans have a defect in myocardial FA uptake (14, 15) that is similar in magnitude to that observed in the CD36-...

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Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation

Cited by 216 publications

References 30 publications

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

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

Diminished Hepatic Gluconeogenesis via Defects in Tricarboxylic Acid Cycle Flux in Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α)-deficient Mice

Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

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