Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice

Tomoaki Inoue, Kunihisa Kobayashi, Toyoshi Inoguchi, Noriyuki Sonoda, Yasutaka Maeda, Eiichi Hirata, Yoshinori Fujimura, Daisuke Miura, Ken ichi Hirano, Ryoichi Takayanagi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2'-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice.

Original languageEnglish
Pages (from-to)224-229
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume438
Issue number1
DOIs
Publication statusPublished - Aug 16 2013

Fingerprint

Diabetic Cardiomyopathies
Lipase
Triglycerides
Down-Regulation
Genes
Oxidative stress
Oxidative Stress
Diacylglycerol O-Acyltransferase
Sterol Regulatory Element Binding Protein 1
Apoptosis
Lipids
Diglycerides
Medical problems
Lipid Metabolism
Left Ventricular Function
Modulators
Myocardium
Deposits
Tissue
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice. / Inoue, Tomoaki; Kobayashi, Kunihisa; Inoguchi, Toyoshi; Sonoda, Noriyuki; Maeda, Yasutaka; Hirata, Eiichi; Fujimura, Yoshinori; Miura, Daisuke; Hirano, Ken ichi; Takayanagi, Ryoichi.

In: Biochemical and Biophysical Research Communications, Vol. 438, No. 1, 16.08.2013, p. 224-229.

Research output: Contribution to journalArticle

Inoue, Tomoaki ; Kobayashi, Kunihisa ; Inoguchi, Toyoshi ; Sonoda, Noriyuki ; Maeda, Yasutaka ; Hirata, Eiichi ; Fujimura, Yoshinori ; Miura, Daisuke ; Hirano, Ken ichi ; Takayanagi, Ryoichi. / Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice. In: Biochemical and Biophysical Research Communications. 2013 ; Vol. 438, No. 1. pp. 224-229.
@article{5c448f192dfc4add9461afb51fa53d81,
title = "Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice",
abstract = "Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2'-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice.",
author = "Tomoaki Inoue and Kunihisa Kobayashi and Toyoshi Inoguchi and Noriyuki Sonoda and Yasutaka Maeda and Eiichi Hirata and Yoshinori Fujimura and Daisuke Miura and Hirano, {Ken ichi} and Ryoichi Takayanagi",
year = "2013",
month = "8",
day = "16",
doi = "10.1016/j.bbrc.2013.07.063",
language = "English",
volume = "438",
pages = "224--229",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice

AU - Inoue, Tomoaki

AU - Kobayashi, Kunihisa

AU - Inoguchi, Toyoshi

AU - Sonoda, Noriyuki

AU - Maeda, Yasutaka

AU - Hirata, Eiichi

AU - Fujimura, Yoshinori

AU - Miura, Daisuke

AU - Hirano, Ken ichi

AU - Takayanagi, Ryoichi

PY - 2013/8/16

Y1 - 2013/8/16

N2 - Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2'-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice.

AB - Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2'-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice.

UR - http://www.scopus.com/inward/record.url?scp=84881550217&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881550217&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2013.07.063

DO - 10.1016/j.bbrc.2013.07.063

M3 - Article

C2 - 23886955

AN - SCOPUS:84881550217

VL - 438

SP - 224

EP - 229

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -