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PLoS One. 2017;12(10):e0186021.

Small heterodimer partner (SHP) deficiency protects myocardia from lipid accumulation in high fat diet-fed mice.

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제1저자 온정헌, 황지연 · 교신저자 문민경

PMID 29016649 PMC5634594 DOI 10.1371/journal.pone.0186021 IF 2.8 내분비대사내과
소속 (8)
  1. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
  2. Preclinical Research Center, Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
  3. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
  4. Department of Internal Medicine, Boramae Medical Center, Seoul, Republic of Korea.
  5. Department of Internal Medicine, Chung-Ang University Hospital, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
  6. Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
  7. Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
  8. Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

Abstract

The small heterodimer partner (SHP) regulates fatty acid oxidation and lipogenesis in the liver by regulating peroxisome proliferator-activated receptor (PPAR) γ expression. SHP is also abundantly expressed in the myocardium. We investigated the effect of SHP expression on myocardia assessing not only heart structure and function but also lipid metabolism and related gene expression in a SHP deletion animal model. Transcriptional profiling with a microarray revealed that genes participating in cell growth, cytokine signalling, phospholipid metabolism, and extracellular matrix are up-regulated in the myocardia of SHP knockout (KO) mice compared to those of wild-type (WT) mice (nominal p value < 0.05). Consistent with these gene expression changes, the left ventricular masses of SHP KO mice were significantly higher than WT mice (76.8 ± 20.5 mg vs. 52.8 ± 6.8 mg, P = 0.0093). After 12 weeks of high fat diet (HFD), SHP KO mice gained less weight and exhibited less elevation in serum-free fatty acid and less ectopic lipid accumulation in the myocardium than WT mice. According to microarray analysis, genes regulated by PPARγ1 and PPARα were down-regulated in myocardia of SHP KO mice compared to their expression in WT mice after HFD, suggesting that the reduction in lipid accumulation in the myocardium resulted from a decrease in lipogenesis regulated by PPARγ. We confirmed the reduced expression of PPARγ1 and PPARα target genes such as CD36, medium-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, and very long-chain acyl-CoA dehydrogenase by SHP KO after HFD.

Figures

Fig 1
Fig 1 Network of significantly altered biological pathways in the myocardia of SHP KO mice compared to in WT mice. Nodes represent gene sets or pathways, and edges are connected if the two gene sets share a significant number of genes (Jaccard coefficient > 0.6). Gene sets with up-regulated and down-regulated genes in SHP KO mice are coloured red and blue, respectively.
Fig 2
Fig 2 Changes in gene expression induced by SHP deficiency and/or HFD feeding and myocardial histologies. (A) Expression of cell growth-related genes c-jun, c-fos, and egr-1. n = 5–8 per group; * p < 0.05 compared to CD WT mice, ** p < 0.05 compared to HFD WT mice. c-jun, c-Jun-N-terminal kinase; egr-1, early growth response 1. (B) Expression of pathologic hypertrophic markers BNP, Acta1, and Serca2a, normalized to β-actin. n = 5–8 per group; * p < 0.05 compared to CD WT mice, † p < 0.05 compared to CD SHP KO mice. BNP, brain natriuretic peptide; Acta1, actin a1 skeletal muscle; Serca2a, sarco/endoplasmic reticulum Ca2+-transport ATPase2a. (C) Myocardial histology of WT and SHP KO mice. Representative myocardial sections of SHP KO mice and WT mice stained with haematoxylin and eosin (H&E). Original magnification, ×200.
Fig 3
Fig 3 Glucose tolerance and changes in insulin resistance-related genes in the myocardia of WT and SHP KO mice after 12 weeks of HFD feeding. (A) Growth curves in mice. *p < 0.05, ** p < 0.001. (B) Intraperitoneal glucose tolerance tests (IPGTTs) (2 g D-glucose per kg body weight) were performed in 17- to 18-week-old male mice. (C) Relative expression of insulin signalling-related genes FOXO3 and PTEN. n = 5–8 per group; * p < 0.05 compared to CD WT mice, † p < 0.05 compared to CD SHP KO mice. FOXO3, forkhead box O3; PTEN, phosphatase and tensin homolog. (D) Relative expression of SHP in WT mice myocardia. n = 5–8 per group; * p < 0.05 compared to CD WT mice.
Fig 4
Fig 4 Myocardial lipid accumulation, FAO, and related gene expression in the myocardia of WT and SHP KO mice after 12 weeks of HFD feeding. (A) Lipid droplets in the myocardia of HFD SHP KO and HFD WT mice. Transmission electron microscope images in HFD SHP KO and HFD WT mice and calculated areas of lipid droplets per unit cardiac muscle. Magnifications of large pictures are 10,000× and those of small ones are 500,000×. n = 8 per group; *p < 0.01. (B) Myocardial fatty acid oxidation and VO2 max in SHP KO and WT mice fed with HFD. n = 5–8 per group. (C) Expression of PPARγ1 and PPARα target genes CD36, MCAD, LCAD, and VLCAD in HFD SHP KO mice. n = 5–8 per group; *p < 0.05 compared to corresponding WT mice. PPARγ1, peroxisome proliferator-activated receptor γ1; CD36, cluster of differentiation; MCAD, medium-chain acyl-CoA dehydrogenase; LCAD, long-chain acyl-CoA dehydrogenase; VLCAD, very long-chain acyl-CoA dehydrogenase. (D) Expression of GLUTs and PDK4 in WT and SHP KO mice. n = 5–8 per group; *p < 0.05 compared to corresponding WT mice. GLUT1, glucose transporter 1; GLUT4, glucose transporter 4; PDK4, pyruvate dehydrogenase kinase 4.

그림 출처: PubMed Central 공개 논문 (PMC5634594)

Conflict of interest statement

Competing Interests:The authors have declared that no competing interests exist.

그 밖의 정보
출판 형태
Journal Article
저널
PloS one · eISSN 1932-6203
전자 출판
2017-10-10
MeSH
Acyl-CoA Dehydrogenase / genetics / metabolism · Acyl-CoA Dehydrogenase, Long-Chain / deficiency / genetics / metabolism · Animals · CD36 Antigens / genetics / metabolism · Congenital Bone Marrow Failure Syndromes · Cytokines / genetics / metabolism · Diet, High-Fat · Fatty Acids / metabolism · Gene Expression Profiling · Lipid Metabolism, Inborn Errors / genetics / metabolism · Lipogenesis / genetics · Liver / metabolism / pathology · Male · Mice · Mice, Knockout · Mitochondrial Diseases / genetics / metabolism · Muscular Diseases / genetics / metabolism · Myocardium / metabolism / pathology · Obesity / etiology / genetics / metabolism / pathology · Oligonucleotide Array Sequence Analysis · PPAR alpha / genetics / metabolism · PPAR gamma / genetics / metabolism · Protective Factors · Receptors, Cytoplasmic and Nuclear / deficiency / genetics · Signal Transduction · Transcriptome*
Substances
CD36 Antigens · Cytokines · Fatty Acids · PPAR alpha · PPAR gamma · Receptors, Cytoplasmic and Nuclear · nuclear receptor subfamily 0, group B, member 2 · Acyl-CoA Dehydrogenase · Acyl-CoA Dehydrogenase, Long-Chain
참고문헌
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