Genetic mutations in adipose triglyceride lipase and myocardial up-regulation of peroxisome proliferated activated receptor-γ in patients with triglyceride deposit cardiomyovasculopathy

Ken Ichi Hirano, Tatsuya Tanaka, Yoshihiko Ikeda, Satoshi Yamaguchi, Nobuhiro Zaima, Kazuhiro Kobayashi, Akira Suzuki, Yasuhiko Sakata, Yasushi Sakata, Kunihisa Kobayashi, Tatsushi Toda, Norihide Fukushima, Hatsue Ishibashi-Ueda, Daniela Tavian, Hironori Nagasaka, Shu Ping Hui, Hitoshi Chiba, Yoshiki Sawa, Masatsugu Hori

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


Adipose triglyceride lipase (ATGL, also known as PNPLA2) is an essential molecule for hydrolysis of intracellular triglyceride (TG). Genetic ATGL deficiency is a rare multi-systemic neutral lipid storage disease. Information regarding its clinical profile and pathophysiology, particularly for cardiac involvement, is still very limited. A previous middle-aged ATGL-deficient patient in our institute (Case 1) with severe heart failure required cardiac transplantation (CTx) and exhibited a novel phenotype, "Triglyceride deposit cardiomyovasculopathy (TGCV)". Here, we tried to elucidate molecular mechanism underlying TGCV. The subjects were two cases with TGCV, including our second case who was a 33-year-old male patient (Case 2) with congestive heart failure requiring CTx. Case 2 was homozygous for a point mutation in the 5′ splice donor site of intron 5 in the ATGL, which results in at least two types of mRNAs due to splicing defects. The myocardium of both patients (Cases 1 and 2) showed up-regulation of peroxisome proliferated activated receptors (PPARs), key transcription factors for metabolism of long chain fatty acids (LCFAs), which was in contrast to these molecules' lower expression in ATGL-targeted mice. We investigated the intracellular metabolism of LCFAs under human ATGL-deficient conditions using patients' passaged skin fibroblasts as a model. ATGL-deficient cells showed higher uptake and abnormal intracellular transport of LCFA, resulting in massive TG accumulation. We used these findings from cardiac specimens and cell-biological experiments to construct a hypothetical model to clarify the pathophysiology of the human disorder. In patients with TGCV, even when hydrolysis of intracellular TG is defective, the marked up-regulation of PPARγ and related genes may lead to increased uptake of LCFAs, the substrates for TG synthesis. This potentially vicious cycle of LCFAs could explain the massive accumulation of TG and severe clinical course for this rare disease.

Original languageEnglish
Pages (from-to)574-579
Number of pages6
JournalBiochemical and biophysical research communications
Issue number2
Publication statusPublished - 2014 Jan 10
Externally publishedYes


  • Adipose triglyceride lipase
  • Long chain fatty acids
  • Peroxisome proliferated activated receptors
  • Triglyceride
  • Triglyceride deposit cardiomyovasculopathy

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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