Fatty Liver Is Associated with Transcriptional Downregulation of Stearoyl-CoA Desaturase and Impaired Protein Dimerization

Tomas Fernández Gianotti,Silvia Sookoian,Carlos Jose Pirola,Adriana Burgueño,Noelia Gonzales Mansilla

doi:10.1371/journal.pone.0076912

Tomas Fernández Gianotti, Silvia Sookoian + Show 3 more

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https://doi.org/10.1371/journal.pone.0076912

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Abstract

Aims and MethodsWe evaluated the modulation of liver stearoyl-CoA desaturase-1 (Scd1) by dietary factors and insulin resistance (IR) in two experimental models of high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). The first model included Sprague Dawley (SD) rats that developed NAFLD without IR, and the second one included a rat model of genetic IR and cardiovascular disease, the spontaneously hypertensive rats (SHR) and its normotensive, insulin-sensitive control Wistar-Kyoto (WKY). The adult rats were given standard chow diet (CD) or HFD for 10 weeks. In all the animals, we explored the hepatic Scd1 transcriptional activity and protein levels.ResultsHFD-fed rats of both strains developed severe NAFLD. Liver abundance of Scd1 mRNA was significantly decreased in HFD-fed rats regardless of the strain; SD-CD: 235±195 vs. SD-HFD 4.5±2.9, p<0.0004, and SHR-CD: 75.6±10.8 vs. SHR-HFD: 4.48±17.4, and WKY-CD: 168.7±17.4 vs. WKY-HFD: 12.9±17.4, p<0.000001 (mean±SE, ANCOVA adjusted by HOMA). Analysis of liver Scd1 protein expression showed a particular pattern in the HFD groups, characterized by the presence of high levels of a monomeric protein band (32.2–36.6 Kda, p<0.003) and decreased levels of a dimeric protein band (61.9–66.1 Kda, p<0.02) regardless of the rat strain. Pharmacologic intervention with the peroxisome proliferator-activated receptor α agonist clofibrate reverted the liver phenotype and significantly modified the hepatic Scd1 transcriptional activity and protein expression.ConclusionDiet-induced fatty liver is associated with the downregulation of hepatic Scd1 transcript and de-dimerization of the protein, and these changes were not much affected by the status of peripheral IR.

Highlights

Stearoyl-CoA desaturase (SCD), known as fatty acid desaturase or delta (9)-desaturase, is a microsomal enzyme involved in the biosynthesis of monounsaturated fatty acids (MUFAs), primarily oleate (C18:1) and palmitoleate (C16:1)
We observed that diet-induced nonalcoholic fatty liver disease (NAFLD) is associated with a dramatic decrease in stearoyl-CoA desaturase-1 (Scd1)-mRNA abundance, which was not affected by the status of peripheral insulin resistance (IR)
high-fat diet (HFD) produced a significant downregulation of liver Scd1 mRNA in both experimental models; this was associated with changes in Scd1 protein expression, which behaved in a similar fashion

Summary

Introduction

Stearoyl-CoA desaturase (SCD), known as fatty acid desaturase or delta (9)-desaturase, is a microsomal enzyme involved in the biosynthesis of monounsaturated fatty acids (MUFAs), primarily oleate (C18:1) and palmitoleate (C16:1). Previous in vitro studies have shown that SCD1 depletion leads to decreased synthesis of MUFAs and phospholipids and promotes the accumulation of saturated fatty acid-enriched unesterified fatty acids and triacylglycerol [7]. Scd inhibition in mice promotes atherosclerosis, reduces HDL cholesterol, and produces a significant enrichment of saturated free fatty acids, and the majority of these changes are originated in tissues involved in lipid biosynthesis, such as the liver [8]

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