Abnormal Lipid Metabolism in Cystathionine β-Synthase-deficient Mice, an Animal Model for Hyperhomocysteinemia

Namekata, Kazuhiko; Enokido, Yasushi; Ishii, Isao; Nagai, Yasuo; Harada, Takayuki; Kimura, Hideo

doi:10.1074/jbc.m406820200

Cited by 136 publications

(145 citation statements)

References 42 publications

(45 reference statements)

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“…We find that dCBS and TSP activity promote fat deposition in flies. This is reminiscent of the metabolic consequences of transsulfuration in mammals, in which hepatic CBS enzyme activity was significantly reduced when mice were fed a high-fat/high-sucrose diet (43) and CBS deficiency induced dysregulation of genes involved in hepatic lipid homeostasis (44,45).…”

Section: Discussionmentioning

confidence: 99%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

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

129

154

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The mechanisms through which dietary restriction enhances health and longevity in diverse species are unclear. The transsulfuration pathway (TSP) is a highly conserved mechanism for metabolizing the sulfur-containing amino acids, methionine and cysteine. Here we show that Drosophila cystathionine β-synthase (dCBS), which catalyzes the rate-determining step in the TSP, is a positive regulator of lifespan in Drosophila and that the pathway is required for the effects of diet restriction on animal physiology and lifespan. dCBS activity was up-regulated in flies exposed to reduced nutrient conditions, and ubiquitous or neuron-specific transgenic overexpression of dCBS enhanced longevity in fully fed animals. Inhibition of the TSP abrogated the changes in lifespan, adiposity, and protein content that normally accompany diet restriction. RNAi-mediated knockdown of dCBS also limited lifespan extension by diet. Diet restriction reduced levels of protein translation in Drosophila, and we show that this is largely caused by increased metabolic commitment of methionine cycle intermediates to transsulfuration. However, dietary supplementation of methionine restored normal levels of protein synthesis to restricted animals without affecting lifespan, indicating that global reductions in translation alone are not required for diet-restriction longevity. Our results indicate a mechanism by which dietary restriction influences physiology and aging.hydrogen sulfide | essential amino acids | metabolism | healthspan F or a broad range of taxonomically diverse organisms, the quality of their diet acts as a powerful modulator of health and longevity through molecular mechanisms that are largely unknown. Lifespan is extended, for example, when food is restricted to an extent that falls short of inducing starvation. In mammals, this manipulation, which is often called dietary restriction (DR), not only increases lifespan but also imparts a broad-spectrum improvement in health during aging. In humans, for example, DR reduces risk factors for diabetes, cardiovascular disease, and cancer (1).Transsulfuration is an evolutionarily ancient metabolic process that involves a network of enzymes responsible for the metabolism of sulfur-containing amino acids. The transsulfuration pathway (TSP) has been studied extensively in mammals, in which it has been shown to direct the conversion of homocysteine to cysteine following the breakdown of methionine, an essential amino acid. Flux through the TSP is known to affect overall cellular metabolism by directly influencing cysteine and methionine levels. Methionine availability affects protein synthesis and methylation, and it has been implicated in murine aging (2). Cysteine availability controls the synthesis of glutathione (GSH), which is the chief regulator of cellular redox homeostasis and an important agent in xenobiotic detoxification (Fig. 1A). Patients with genetic defects in the TSP are characterized by high levels of homocysteine, low levels of GSH, and increased incidence of age-related path...

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Section: Discussionmentioning

confidence: 99%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

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

129

154

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“…Routine histological examinations of major organs did not reveal any specific abnormality in either Cth ϩ/Ϫ or Cth Ϫ/Ϫ mice (data not shown). Unlike Cbs Ϫ/Ϫ mice (15,16), Cth Ϫ/Ϫ mice were free of hepatic steatosis (data not shown). This observation was supported by serum biochemistry in which normal levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, total and free cholesterol, triglyceride, nonesterified fatty acid, phospholipid, and lecithin-cholesterol acyltransferase activity were obtained; all of the biochemical parameters were dramatically elevated in Cbs Ϫ/Ϫ mice (supplemental Table S1).…”

Section: No Apparent Abnormality In Cthmentioning

confidence: 99%

“…Mouse CTH was detected using both anti-CTH amino terminus and carboxyl terminus rabbit polyclonal antibodies that recognize amino acids 1-193 and 194 -398 of a rat 398-amino acid CTH protein, respectively (21). Mouse CBS was detected with anti-rat CBS rabbit polyclonal antibody (15).…”

Section: Methodsmentioning

confidence: 99%

“…Serum levels of total and free cholesterol, triglyceride, nonesterified fatty acid, and phospholipid, were measured with enzymatic assay kits from Wako (Osaka, Japan) (15,16). Serum lecithin-cholesterol acyltransferase activity was measured using the Anasolve lecithin-cholesterol acyltransferase (Sekisui Medical, Tokyo, Japan) (15,16).…”

Section: Methodsmentioning

confidence: 99%

“…Ϫ/Ϫ Mice-The vast majority of Cbs Ϫ/Ϫ mice die before 4 weeks of age (15,16), and thus, 2-week-old pups derived from heterozygous mating were examined for their amino acid levels in serum (Table 1) or urine. Serum cystathionine levels in Cth Ϫ/Ϫ were as high as 500 M, whereas those in others were below detectable levels ( Table 1).…”

Section: Hypercystathioninemia/hyperhomocysteinemia But Not Hypermethmentioning

confidence: 99%

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Cystathionine γ-Lyase-deficient Mice Require Dietary Cysteine to Protect against Acute Lethal Myopathy and Oxidative Injury

Ishii

Akahoshi

Yamada

et al. 2010

Journal of Biological Chemistry

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206

229

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Cysteine is considered a nonessential amino acid in mammals as it is synthesized from methionine via trans-sulfuration. However, premature infants or patients with hepatic failure may require dietary cysteine due to a lack of cystathionine ␥-lyase (CTH), a key trans-sulfuration enzyme. Here, we generated CTH-deficient (Cth ؊/؊ ) mice as an animal model of cystathioninemia/cystathioninuria. Cth ؊/؊ mice developed normally in general but displayed hypercystathioninemia/hyperhomocysteinemia though not hypermethioninemia. When fed a low cyst(e)ine diet, Cth ؊/؊ mice showed acute skeletal muscle atrophy (myopathy) accompanied by enhanced gene expression of asparagine synthetase and reduced contents of glutathione in livers and skeletal muscles, and intracellular accumulation of LC3 and p62 in skeletal myofibers; they finally died of severe paralysis of the extremities. Cth ؊/؊ hepatocytes required cystine in a culture medium and showed greater sensitivity to oxidative stress. Cth ؊/؊ mice exhibited systemic vulnerability to oxidative injury, which became more prominent when they were fed the low cyst(e)ine diet. These results reveal novel roles of trans-sulfuration previously unrecognized in mice lacking another trans-sulfuration enzyme cystathionine ␤-synthase (Cbs ؊/؊ ). Because Cbs ؊/؊ mice display hyperhomocysteinemia and hypermethioninemia, our results raise questions against the homocysteine-based etiology of CBS deficiency and the current newborn screening for homocysteinemia using Guthrie's method, which detects hypermethioninemia.

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Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to promote hepatic steatosis in mice

et al. 2016

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Hyperhomocysteinemia (HHcy) is associated with liver diseases such as fatty liver and hepatic fibrosis; however, the underlying mechanism is still largely unknown. The current study aimed to explore the signaling pathway involved in HHcyinduced hepatic steatosis (HS). C57BL/6 mice were fed a high-methionine diet (HMD) for 4 and 8 weeks to establish the HHcy mouse model. Compared to a chow diet, the HMD induced hepatic steatosis and elevated hepatic expression of CD36, a fatty acid transport protein. The increased CD36 expression was associated with activation of the aryl hydrocarbon receptor (AHR). In primary cultured hepatocytes, high levels of homocysteine (Hcy) treatment up-regulated CD36 and increased subsequent lipid uptake; both were significantly attenuated by small interfering RNA (siRNA) knockdown of CD36 and AHR. Chromatin immunoprecipitation assay revealed that Hcy promoted binding of AHR to the CD36 promoter, and transient transfection assay demonstrated markedly increased activity of the AHR response element by Hcy, which was ligand dependent. Mass spectrometry revealed significantly increased hepatic content of lipoxin A 4 (LXA 4 ), a metabolite of arachidonic acid, in HMD-fed mice. Furthermore, overexpression of 15-oxoprostaglandin 13-reductase 1, a LXA 4 inactivation enzyme, inhibited Hcy-induced AHR activation, lipid uptake, and lipid accumulation. Moreover, LXA 4 -induced up-regulation of CD36 and lipid uptake was inhibited by AHR siRNA in vitro in hepatocytes. Finally, treatment with an AHR antagonist reversed HHcy-induced lipid accumulation by inhibiting the AHR-CD36 pathway in mice. Conclusion: HHcy activates the AHR-CD36 pathway by increasing hepatic LXA 4 content, which results in hepatic steatosis. (HEPATOLOGY 2016;64:92-105) N onalcoholic fatty liver disease (NAFLD) is an increasingly recognized disease status that involves a spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Obesity, type 2 diabetes mellitus, and hyperlipidemia are important risk factors of NAFLD, but the pathogenesis of NAFLD is poorly understood. (1) Homocysteine (Hcy) is a toxic Abbreviations: 15d-PGJ2, 15-deoxy-D12,14-prostaglandin J2; 15-oxo-ETE, 15-oxo-eicosatetraenoic acid; 3-MC, 3

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Abnormal Lipid Metabolism in Cystathionine β-Synthase-deficient Mice, an Animal Model for Hyperhomocysteinemia

Cited by 136 publications

References 42 publications

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Cystathionine γ-Lyase-deficient Mice Require Dietary Cysteine to Protect against Acute Lethal Myopathy and Oxidative Injury

Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to promote hepatic steatosis in mice

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