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

Jung Hun Ohn,Hwan Hee Kim,Min Kyong Moon,Kwang-Il Kim,Young Do Koo,Hyuk Jae Chang,Hwa Young Ahn,Young Joo Park,Hak Chul Jang,Ji Yeon Hwang,Hye Seung Lee,Catherine Mounier

doi:10.1371/journal.pone.0186021

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.

Highlights

The small heterodimer partner (SHP) is an atypical orphan nuclear receptor that regulates the expression of genes involved in glucose, lipid, and bile acid metabolism and plays a key role in metabolic homeostasis [1, 2]
We found that SHPdeficient mice hearts hypertrophied without functional change and exhibited less ectopic lipid accumulation after a high fat diet (HFD), likely resulting from a reduction in lipogenesis regulated by peroxisome proliferator-activated receptor γ (PPARγ)
SHP deficiency induced cardiac hypertrophy, and consistent with this, up-regulation of genes involved in cell growth, cytokine signalling, phospholipid metabolism, and extracellular matrix (ECM) in the heart tissue of SHP KO mice

Summary

Introduction

The small heterodimer partner (SHP) is an atypical orphan nuclear receptor that regulates the expression of genes involved in glucose, lipid, and bile acid metabolism and plays a key role in metabolic homeostasis [1, 2]. SHP-deficient mice exhibit increased fatty acid oxidation (FAO) and decreased lipogenesis, and are protected from diet-induced hepatic steatosis [3,4,5,6,7]. This is associated with the activation of peroxisome proliferator-activated receptor γ (PPARγ) by SHP [8]. In SHP-deficient mice, very low expression of PPARγ2, a potent lipogenic transcription factor, decreases lipogenesis in the liver [7]. Heart energy is primarily derived from FAO, and long-chain fatty acids (LCFAs) are the preferred substrate for oxidative phosphorylation in cardiac mitochondria [9, 10]. It was recently reported that SHP overexpression in cardiomyocytes induced lipid accumulation, insulin resistance, and inflammation [12]

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Results

Conclusion