Effect of diet composition on coenzyme A and its thioester pools in various rat tissues

Tokutake, Yuka; Iio, Wataru; Onizawa, Naoki; Ogata, Yuta; Kohari, Daisuke; Toyoda, Atsushi; Chohnan, Shigeru

doi:10.1016/j.bbrc.2012.06.037

Cited by 16 publications

(19 citation statements)

References 21 publications

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“…To understand whether malonyl-CoA’s effects on glycolytic enzymes may stem from covalent non-enzymatic malonylation, we performed parallel assessments of GAPDH malonylation and activity as a function of time. Time-dependent enzyme activity loss was minimized by performing these analyses at 200 μM, which likely represents the upper range of physiologically relevant malonyl-CoA concentrations (Henry et al, 2015; Tokutake et al, 2012; Tokutake et al, 2010). Consistent with a covalent inhibition mechanism, malonyl-CoA reduces GAPDH activity in a time-dependent manner (Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling

Kulkarni

Worth

Zengeya

et al. 2017

Cell Chemical Biology

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SUMMARY Non-enzymatic protein modification driven by thioester reactivity is thought to play a major role in the establishment of cellular lysine acylation. However, the specific protein targets of this process are largely unknown. Here we report an experimental strategy to investigate non-enzymatic acylation in cells. Specifically, we develop a chemoproteomic method that separates thioester reactivity from enzymatic utilization, allowing selective enrichment of non-enzymatic acylation targets. Applying this method to cancer cell lines identifies numerous candidate targets of non-enzymatic acylation, including several enzymes in lower glycolysis. Functional studies highlight malonyl-CoA as a reactive thioester metabolite that can modify and inhibit glycolytic enzyme activity. Finally, we show that synthetic thioesters can be used as novel reagents to probe non-enzymatic acylation in living cells. Our studies provide new insights into the targets and drivers of non-enzymatic acylation, and demonstrate the utility of reactivity-based methods to experimentally investigate this phenomenon in biology and disease.

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Section: Resultsmentioning

confidence: 99%

Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling

Kulkarni

Worth

Zengeya

et al. 2017

Cell Chemical Biology

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“…Potentially fatal valproic acid therapy-induced hepatic dysfunction, which is associated with impaired β-oxidation of fatty acids and ketogenesis due to sequestration of CoASH into poorly metabolized valproyl CoA, can be prevented by administration of CoASH precursors (53,54). In rodents, hepatic CoASH concentrations decrease in response to an HFD (55), while the concentration of pantothenic acid actually increases (56), suggesting that hepatic CoASH homeostasis is dysregulated in obesity. De novo CoASH synthesis is required for life in mice, and impaired CoASH synthesis is associated with fasting-induced hepatic steatosis (57,58).…”

Section: Discussionmentioning

confidence: 99%

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

et al. 2014

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R e s e a R c h a R t i c l e5 1Ketogenic insufficiency causes hepatic inflammation, injury, and altered glucose metabolism in the setting of carbohydrate-replete overnutrition. To determine the effects of ketogenic insufficiency in the context of overnutrition, mice previously receiving ASOs for 2 weeks while on a standard low-fat chow diet were then maintained for 8 weeks on a 60% high-fat diet (HFD) commonly used to induce hyperglycemia, hepatic steatosis, and inflammation in WT mice. HMGCS2 immunoblots indicated that hepatic HMGCS2 mice (Supplemental Figure 2, A-C). HMGCS2 ASO-treated mice also exhibited normal serum free fatty acid (FFA) and TAG concentrations and a normal physiologic distribution of residual βOHB and AcAc (Supplemental Figure 2, D-F). Interestingly, HMGCS2 ASO-treated mice displayed mild, but very consistently elevated, blood glucose concentrations (160.9 ± 3.2 mg/dl vs. 145.0 ± 3.4 mg/dl in controls, n = 28-36/group, P = 0.0013), without changes in serum insulin concentrations (Supplemental Figure 2, G and H). C]pyruvate, quantified by NMR profiling of perfused liver extracts from ASO-treated mice fed a 60% HFD for 8 weeks. n = 4-5/group. *P < 0.05, **P < 0.01, ***P < 0.001 by Student's t test.

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“…The concentration of malonyl‐CoA was measured using the acyl‐CoA cycling method (Tokutake et al . ). Malonyl‐CoA was extracted from the hypothalamus by homogenization in 0.6 mol/L H 2 SO 4 .…”

Section: Methodsmentioning

confidence: 97%

Effects of chronic mild food restriction on behavior and the hypothalamic malonyl‐CoA signaling pathway

Iio

Tokutake

Koike

et al. 2014

Animal Science Journal

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Depression induces anorexia, leading to suppressed feeding behaviors and energy intake. Previously, we revealed that chronic social defeat induced a mild suppression of feeding in rats with elevated levels of hypothalamic malonyl-CoA which regulates feeding. Therefore, we attempted to elucidate the effects of chronic mild food restriction on behavior and on hypothalamic malonyl-CoA. The chronic mild food restricted rats were fed a restricted diet approximately 80% to 90% amount of diet compared to the control for 5 weeks. Ratios of restriction were adjusted with feed consumption in the chronic social defeat stressed rats. Chronic mild food restricted rats exhibited a suppression of body weight gain similar to that of the chronic social defeat stressed rats. Also these rats showed increased time spent in the center area of an open field (OF), prolonged immobility time in forced swim, increased phosphorylation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase and a decreased concentration of hypothalamic malonyl-CoA. Weight of the adrenal glands, locomotion in an OF, mitogen-activated protein kinase cascade and calcium/calmodulin-dependent protein kinases II in the hippocampus were not affected by chronic mild food restriction. Our findings suggest that chronic mild food restriction activates AMPK following a decreased hypothalamic malonyl-CoA.

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Effect of diet composition on coenzyme A and its thioester pools in various rat tissues

Cited by 16 publications

References 21 publications

Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling

Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Effects of chronic mild food restriction on behavior and the hypothalamic malonyl‐CoA signaling pathway

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