Hepatic Transcriptome Profiling Reveals Lack of Acsm3 Expression in Polydactylous Rats with High-Fat Diet-Induced Hypertriglyceridemia and Visceral Fat Accumulation.

Kristýna Junková,Michal Pravenec,Jan Šilhavý,Denisa Miklánková,Lukáš F Mirchi,Michaela Janků,Irena Marková,Martina Hüttl,Hana Malínská,František Liška,Josef Včelák,Blanka Chylíková,Ondřej Šeda

doi:10.3390/nu13051462

Abstract

Metabolic syndrome (MetS) is an important cause of worldwide morbidity and mortality. Its complex pathogenesis includes, on the one hand, sedentary lifestyle and high caloric intake, and, on the other hand, there is a clear genetic predisposition. PD (Polydactylous rat) is an animal model of hypertriglyceridemia, insulin resistance, and obesity. To unravel the genetic and pathophysiologic background of this phenotype, we compared morphometric and metabolic parameters as well as liver transcriptomes among PD, spontaneously hypertensive rat, and Brown Norway (BN) strains fed a high-fat diet (HFD). After 4 weeks of HFD, PD rats displayed marked hypertriglyceridemia but without the expected hepatic steatosis. Moreover, the PD strain showed significant weight gain, including increased weight of retroperitoneal and epididymal fat pads, and impaired glucose tolerance. In the liver transcriptome, we found 5480 differentially expressed genes, which were enriched for pathways involved in fatty acid beta and omega oxidation, glucocorticoid metabolism, oxidative stress, complement activation, triacylglycerol and lipid droplets synthesis, focal adhesion, prostaglandin synthesis, interferon signaling, and tricarboxylic acid cycle pathways. Interestingly, the PD strain, contrary to SHR and BN rats, did not express the Acsm3 (acyl-CoA synthetase medium-chain family member 3) gene in the liver. Together, these results suggest disturbances in fatty acid utilization as a molecular mechanism predisposing PD rats to hypertriglyceridemia and fat accumulation.

Highlights

IntroductionMetabolic syndrome (MetS) is a worldwide health problem and major risk factor in cardiovascular morbidity and mortality with multifactorial pathogenesis, combining the extrinsic (environment, lifestyle, diet, energy expenditure) and intrinsic (genetic background) factors and their mutual interactions
Administration, there was a significant weight gain in the PD strain compared to the other strains and SHR compared to Brown Norway (BN) (Figure 1b,c), reflecting the amount of the consumed diet (Figure 1d)
Tion, there was a significant weight gain in the PD strain compared to the other strains and SHR compared to BN (Figure 1b,c), reflecting the amount of the consumed diet (Figure 1d)

Summary

Introduction

MetS is a worldwide health problem and major risk factor in cardiovascular morbidity and mortality with multifactorial pathogenesis, combining the extrinsic (environment, lifestyle, diet, energy expenditure) and intrinsic (genetic background) factors and their mutual interactions. Large genome-wide association studies (GWASs) in humans are powerful tools to uncover the genetic landscape of MetS and other multifactorial conditions and may promise prospective risk assessment in the future using polygenic risk scores [3]. Human GWASs use very simplistic additive genetic models. A substantial amount of gene–gene interactions and gene–environment interaction effects on disease risk remain buried in the so-called “missing heritability” [4]. Defined animal models can provide a useful alternative to GWAS in dissecting the genetic background of various polygenic traits and gene–gene and gene–environment interactions

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