title: Genetic mutations in adipose triglyceride lipase and myocardial up-regulation of peroxisome proliferated activated receptor-γ in patients with triglyceride deposit cardiomyovasculopathy.
abstract: 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.
authors: Laboratory of Cardiovascular Disease, Novel, Non-Invasive, and Nutritional Therapeutics (CNT), Graduate School of Medicine, Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan; Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: khirano@cnt-osaka.com.
authors: Ken-ichi
authors: K
authors: Hirano
authors: Center for Medical Research and Education, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Tatsuya
authors: T
authors: Tanaka
authors: Department of Pathology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita 565-8565, Japan.
authors: Yoshihiko
authors: Y
authors: Ikeda
authors: Laboratory of Cardiovascular Disease, Novel, Non-Invasive, and Nutritional Therapeutics (CNT), Graduate School of Medicine, Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan; Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Satoshi
authors: S
authors: Yamaguchi
authors: Department of Applied Biochemistry, Kinki University, 3327-204, Nakamachi, Nara 631-8505, Japan.
authors: Nobuhiro
authors: N
authors: Zaima
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors: Kazuhiro
authors: K
authors: Kobayashi
authors: Laboratory of Cardiovascular Disease, Novel, Non-Invasive, and Nutritional Therapeutics (CNT), Graduate School of Medicine, Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan; Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Akira
authors: A
authors: Suzuki
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo-cho, Aoba-ku, Sendai 980-8574, Japan.
authors: Yasuhiko
authors: Y
authors: Sakata
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yasushi
authors: Y
authors: Sakata
authors: Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, 1-1-1, Zokumyoin, Chikushino, Fukuoka 818-8502, Japan.
authors: Kunihisa
authors: K
authors: Kobayashi
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors: Tatsushi
authors: T
authors: Toda
authors: Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Norihide
authors: N
authors: Fukushima
authors: Department of Pathology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita 565-8565, Japan.
authors: Hatsue
authors: H
authors: Ishibashi-Ueda
authors: Laboratory of Cellular Biochemistry and Molecular Biology - CRIBENS, Catholic University of the Sacred Heart, Largo Gemelli 1, Milan 20123, Italy.
authors: Daniela
authors: D
authors: Tavian
authors: Department of Pediatrics, Takarazuka City Hosptial, 4-5-1, Kohama, Takarazuka, Hyogo 665-0827, Japan.
authors: Hironori
authors: H
authors: Nagasaka
authors: Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Sapporo 060-0812, Japan.
authors: Shu-Ping
authors: SP
authors: Hui
authors: Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Sapporo 060-0812, Japan.
authors: Hitoshi
authors: H
authors: Chiba
authors: Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yoshiki
authors: Y
authors: Sawa
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Masatsugu
authors: M
authors: Hori
mesh_terms: D000328:Adult; D009202:Cardiomyopathies / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000217:Acyltransferases
chemical_list: D008049:Lipase; D047495:PPAR gamma; D014280:Triglycerides; C494794:PNPLA2 protein, human; D000217:Acyltransferases
keywords: ATGL; Adipose triglyceride lipase; BSA; CTx; FCS; GAPDH; HE; LCFA; LSM; LVAS; Long chain fatty acids; MEM; PBS; PCR; PPAR; Peroxisome proliferated activated receptors; TGCV; Triglyceride; Triglyceride deposit cardiomyovasculopathy; adipose triglyceride lipase; bovine serum albumin; cardiac transplantation; fetal calf serum; glyceraldehyde-3-phosphate dehydrogenase; hematoxylin and eosin; laser scanning microscopy; left ventricular assist system; long chain fatty acids; modified Eagle’s medium; peroxisome proliferated activated receptors; phosphate buffered saline; polymerase chain reaction; triglyceride deposit cardiomyovasculopathy