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#32750298   2020/07/30 To Up

Increased Glucose Availability Attenuates Myocardial Ketone Body Utilization.

Background Perturbations in myocardial substrate utilization have been proposed to contribute to the pathogenesis of cardiac dysfunction in diabetic subjects. The failing heart in nondiabetics tends to decrease reliance on fatty acid and glucose oxidation, and increases reliance on ketone body oxidation. In contrast, little is known regarding the mechanisms mediating this shift among all 3 substrates in diabetes mellitus. Therefore, we tested the hypothesis that changes in myocardial glucose utilization directly influence ketone body catabolism. Methods and Results We examined ventricular-cardiac tissue from the following murine models: (1) streptozotocin-induced type 1 diabetes mellitus; (2) high-fat-diet-induced glucose intolerance; and transgenic inducible cardiac-restricted expression of (3) glucose transporter 4 (transgenic inducible cardiac restricted expression of glucose transporter 4); or (4) dominant negative -GlcNAcase. Elevated blood glucose (type 1 diabetes mellitus and high-fat diet mice) was associated with reduced cardiac expression of β-hydroxybutyrate-dehydrogenase and succinyl-CoA:3-oxoacid CoA transferase. Increased myocardial β-hydroxybutyrate levels were also observed in type 1 diabetes mellitus mice, suggesting a mismatch between ketone body availability and utilization. Increased cellular glucose delivery in transgenic inducible cardiac restricted expression of glucose transporter 4 mice attenuated cardiac expression of both Bdh1 and Oxct1 and reduced rates of myocardial BDH1 activity and β-hydroxybutyrate oxidation. Moreover, elevated cardiac protein -GlcNAcylation (a glucose-derived posttranslational modification) by dominant negative -GlcNAcase suppressed β-hydroxybutyrate dehydrogenase expression. Consistent with the mouse models, transcriptomic analysis confirmed suppression of BDH1 and OXCT1 in patients with type 2 diabetes mellitus and heart failure compared with nondiabetic patients. Conclusions Our results provide evidence that increased glucose leads to suppression of cardiac ketolytic capacity through multiple mechanisms and identifies a potential crosstalk between glucose and ketone body metabolism in the diabetic myocardium.
Manoja K Brahma, Chae-Myeong Ha, Mark E Pepin, Sobuj Mia, Zhihuan Sun, John C Chatham, Kirk M Habegger, Evan Dale Abel, Andrew J Paterson, Martin E Young, Adam R Wende

1087 related Products with: Increased Glucose Availability Attenuates Myocardial Ketone Body Utilization.

100200100 assays250ul 1 G25 mg500 ml 1KG100 ug100ul25 mg2x96 well plate

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#31105148   2019/05/17 To Up

Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs for diabetes and might prevent heart failure. In this study, we investigated the effects of tofogliflozin, an SGLT2 inhibitor, on cardiac hypertrophy and metabolism in hypertensive rats fed a high-fat diet. Dahl salt-sensitive (DS) rats, hypertensive model rats, and Dahl salt-resistant (DR) rats, non-hypertensive model rats, were fed a high-salt and high-fat diet containing tofogliflozin (0.005%) for 9 weeks to examine the effects of this drug on cardiac hypertrophy and metabolism. Tofogliflozin tended to suppress a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly suppress a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Tofogliflozin reduced cardiac hypertrophy (heart weight/body weight) not only in DS rats but also in DR rats. Histological analysis showed that tofogliflozin significantly decreased cardiomyocyte hypertrophy and perivascular fibrosis in both DS and DR rats. Tofogliflozin significantly decreased the expression levels of genes related to cardiac hypertrophy (encoding for natriuretic peptides A and B and interleukin-6), and to cardiac fibrosis (encoding for transforming growth factor-β1 and collagen type IV), in DS rats. Recent studies have shown that hypertrophied and failing hearts shift to oxidizing ketone bodies as a significant fuel source. We also performed metabolome analysis for ventricular myocardial tissue. Tofogliflozin reduced 3-hydroxybutyrate, a ketone body, and significantly decreased the expression levels of β-hydroxybutyrate dehydrogenase 1 and 3-oxoacid CoA-transferase, which are related to ketone oxidization. In conclusion, tofogliflozin ameliorated cardiac hypertrophy and fibrosis along with reduction of ketone usage in myocardial tissue.
Tomonari Kimura, Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Kaoru Akazawa, Yukihiro Saito, Satoshi Akagi, Yuko Ohno, Megumi Kondo, Daiji Miura, Jun Wada, Hiroshi Ito

1646 related Products with: Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet.

2.5 mg1 mg100 mg 100 G 100 G25 mg 100 G1 mg10 g

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#30940842   2019/04/02 To Up

A new hyperpolarized C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart.

Emerging studies have recently shown the potential importance of ketone bodies in cardio-metabolic health. However, techniques to determine myocardial ketone body utilization in vivo are lacking. In this work, we developed a novel method to assess myocardial ketone body utilization in vivo using hyperpolarized [3-C]acetoacetate and investigated the alterations in myocardial ketone body metabolism in diabetic rats. Within a minute upon injection of [3-C]acetoacetate, the production of [5-C]glutamate and [1-C] acetylcarnitine can be observed real time in vivo. In diabetic rats, the production of [5-C]glutamate was elevated compared to controls, while [1-C]acetylcarnitine was not different. This suggests an increase in ketone body utilization in the diabetic heart, with the produced acetyl-CoA channelled into the tricarboxylic acid cycle. This observation was corroborated by an increase activity of succinyl-CoA:3-ketoacid-CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone body utilization, in the diabetic heart. The increased ketone body oxidation in the diabetic hearts correlated with cardiac hypertrophy and dysfunction, suggesting a potential coupling between ketone body metabolism and cardiac function. Hyperpolarized [3-C]acetoacetate is a new probe with potential for non-invasive and real time monitoring of myocardial ketone body oxidation in vivo, which offers a powerful tool to follow disease progression or therapeutic interventions.
Desiree Abdurrachim, Chern Chiuh Woo, Xing Qi Teo, Wei Xin Chan, George K Radda, Philip Teck Hock Lee

1195 related Products with: A new hyperpolarized C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart.

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#30928098   2019/03/27 To Up

Role of OXCT1 in ovine adipose and preadipocyte differentiation.

3-oxoacid CoA-transferase 1 (OXCT1) is a key enzyme in ketone body metabolism that is expressed in adipose and other tissues. The present study addressed the function of OXCT1 in adipose tissue from Tan sheep. The 1563 bp ovine OXCT1 coding sequence was cloned from ovine adipose tissue. The OXCT1 protein sequence was highly homologous to OXCT1 from other species. OXCT1 was highly expressed in kidney and at lower levels in small intestine, lung, spleen, heart, stomach, liver, tail adipose, and cartilage, but not in longissimus muscle. OXCT1 was expressed at higher levels in perirenal and tail adipose tissues than in subcutaneous adipose tissue. OXCT1 expression levels increased during the in vitro differentiation of adipocytes, but decreased dramatically at day 8. OXCT1 knockdown in ovine adipocytes promoted lipid accumulation, whereas overexpression did the converse. This study demonstrates that OXCT1 may play a role in adipogenesis and provides new insight on adipose deposition in sheep.
Jie Zeng, Shi-Wei Zhou, Jin Zhao, Miao-Han Jin, Dan-Ju Kang, Yu-Xin Yang, Xiao-Long Wang, Yu-Lin Chen

1324 related Products with: Role of OXCT1 in ovine adipose and preadipocyte differentiation.

5 x 50 ug96tests100 μg50 ug 100 UG10 0.1 mg2 100 μg1 mg20 µl (10 mM)

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#30155352   2018/08/21 To Up

Comprehensive analysis of metastasis-related genes reveals a gene signature predicting the survival of colon cancer patients.

The mechanism underlying colon cancer metastasis remain unclear. This study aimed to elucidate the genes alteration during the metastasis of colon cancer and identify genes that crucial to the metastasis and survival of colon cancer patients.
Haotang Wei, Jilin Li, Minzhi Xie, Ronger Lei, Bangli Hu

1537 related Products with: Comprehensive analysis of metastasis-related genes reveals a gene signature predicting the survival of colon cancer patients.



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#31073471   2017/07/19 To Up

A Case of Succinyl-CoA:3-Oxoacid CoA Transferase Deficiency Presenting with Severe Acidosis in a 14-Month-Old Female: Evidence for Pathogenicity of a Point Mutation in the Gene.

We describe a case of succinyl-CoA:3-oxoacid CoA transferase (SCOT) deficiency in an otherwise healthy 14 month-old female. She presented with lethargy, tachypnea, and hyperpnea with hypoglycemia and a severe anion gap metabolic acidosis. Early management included correction of the acidosis and metabolic support with dextrose and insulin. Inborn errors of metabolism are rare outside the neonatal period. However, SCOT deficiency may present at older ages. Maintaining a high index of suspicion, immediate transfer to a pediatric intensive care unit, and prompt metabolic support are key to achieving a favorable outcome.
Daniel J Zheng, Michael Hooper, Michele Spencer-Manzon, Richard W Pierce

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#29414764   2018/02/05 To Up

Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo.

The ketogenic diet (KD) is a high-fat, very-low-carbohydrate diet that triggers a fasting state by decreasing glucose and increasing ketone bodies, such as β-hydroxybutyrate (βHB). In experimental models and clinical trials, the KD has shown anti-tumor effects, possibly by reducing energy supplies to cells, which damage the tumor microenvironment and inhibit tumor growth. Here, we determined expression levels of genes encoding the ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA: 3-oxoacid CoA transferase 1 (OXCT1) in 33 human cancer cell lines. We then selected two representative lines, HeLa and PANC-1, for in vivo examination of KD sensitivity in tumors with high or low expression, respectively, of these two enzymes. In mice with HeLa xenografts, the KD increased tumor growth and mouse survival decreased, possibly because these tumors actively consumed ketone bodies as an energy source. Conversely, the KD significantly inhibited growth of PANC-1 xenograft tumors. βHB added to each cell culture significantly increased proliferation of HeLa cells, but not PANCI-1 cells. Downregulation of both BDH1 and OXCT1 rendered HeLa cells sensitive to the KD in vitro and in vivo. Tumors with low ketolytic enzyme expression may be unable to metabolize ketone bodies, thus predicting a better response to KD therapy.
Jie Zhang, Ping-Ping Jia, Qing-Le Liu, Ming-Hua Cong, Yun Gao, Han-Ping Shi, Wei-Nan Yu, Ming-Yong Miao

2754 related Products with: Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo.

96 tests

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#28695376   2017/07/10 To Up

Heterozygous carriers of succinyl-CoA:3-oxoacid CoA transferase deficiency can develop severe ketoacidosis.

Succinyl-CoA:3-oxoacid CoA transferase (SCOT, gene symbol OXCT1) deficiency is an autosomal recessive disorder in ketone body utilization that results in severe recurrent ketoacidotic episodes in infancy, including neonatal periods. More than 30 patients with this disorder have been reported and to our knowledge, their heterozygous parents and siblings have had no apparent ketoacidotic episodes. Over 5 years (2008-2012), we investigated several patients that presented with severe ketoacidosis and identified a heterozygous OXCT1 mutation in four of these cases (Case1 p.R281C, Case2 p.T435N, Case3 p.W213*, Case4 c.493delG). To confirm their heterozygous state, we performed a multiplex ligation-dependent probe amplification analysis on the OXCT1 gene which excluded the presence of large deletions or insertions in another allele. A sequencing analysis of subcloned full-length SCOT cDNA showed that wild-type cDNA clones were present at reasonable rates to mutant cDNA clones. Over the following 2 years (2013-2014), we analyzed OXCT1 mutations in six more patients presenting with severe ketoacidosis (blood pH ≦7.25 and total ketone body ≧10 mmol/L) with non-specific urinary organic acid profiles. Of these, a heterozygous OXCT1 mutation was found in two cases (Case5 p.G391D, Case6 p.R281C). Moreover, transient expression analysis revealed R281C and T435N mutants to be temperature-sensitive. This characteristic may be important because most patients developed ketoacidosis during infections. Our data indicate that heterozygous carriers of OXCT1 mutations can develop severe ketoacidotic episodes in conjunction with ketogenic stresses.
Hideo Sasai, Yuka Aoyama, Hiroki Otsuka, Elsayed Abdelkreem, Yasuhiro Naiki, Mitsuru Kubota, Yuji Sekine, Masatsune Itoh, Mina Nakama, Hidenori Ohnishi, Ryoji Fujiki, Osamu Ohara, Toshiyuki Fukao

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#28684065   2017/07/04 To Up

The role of OXCT1 in the pathogenesis of cancer as a rate-limiting enzyme of ketone body metabolism.

Cancer cells are well documented to reprogram their metabolism in order to support the maintenance and reproduction. 3-oxoacid CoA-transferase 1 (OXCT1) is a key enzyme in ketone body metabolism that catalyzes the first and rate-determining step of ketolysis. The product of OXCT1 converts to acetyl-CoA and finally fed into the tricarboxylic acid cycle for oxidation and ATP production. However, little is known of its regulation right now. Recently, some studies suggested that OXCT1 participates in tumorigenesis and signaling in cancer cells. Furthermore, our recent work showed that a marked elevation of OXCT1 expression in different categories of cancer cells. Here we review the metabolic functions of OXCT1 and its surprising roles in supporting the biological hallmarks of malignancy. We also review recent efforts in exploring the mechanism responsible for the tumor promoting effect of OXCT1 and suggest a novel therapeutic target for cancer therapy.
Song Zhang, Caifeng Xie

2342 related Products with: The role of OXCT1 in the pathogenesis of cancer as a rate-limiting enzyme of ketone body metabolism.

1900 tests100 100 UG

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