Dietary Olive Oil and Menhaden Oil Mitigate Induction of Lipogenesis in Hyperinsulinemic Corpulent JCR:LA-cp Rats: Microarray Analysis of Lipid-Related Gene Expression

Abstract

In the corpulent James C. Russell corpulent (JCR:LA-cp) rat, hyperinsulinemia leads to induction of lipogenic enzymes via enhanced expression of sterol-regulatory-binding protein (SREBP)-1c. This results in increased hepatic lipid production and hypertriglyceridemia. Information regarding down-regulation of SREBP-1c and lipogenic enzymes by dietary fatty acids in this model is limited. We therefore assessed de novo hepatic lipogenesis and hepatic and plasma lipids in corpulent JCR rats fed diets enriched in olive oil or menhaden oil. Using microarray and Northern analysis, we determined the effect of these diets on expression of mRNA for lipogenic enzymes and other proteins related to lipid metabolism. In corpulent JCR:LA-cp rats, both the olive oil and menhaden oil diets reduced expression of SREBP-1c, with concomitant reductions in hepatic triglyceride content, lipogenesis, and expression of enzymes related to lipid synthesis. Unexpectedly, expression of many peroxisomal proliferator-activated receptor-dependent enzymes mediating fatty acid oxidation was increased in livers of corpulent JCR rats. The menhaden oil diet further increased expression of these enzymes. Induction of SREBP-1c by insulin is dependent on liver x receptor (LXR)alpha. Although hepatic expression of mRNA for LXR itself was not increased in corpulent rats, expression of Cyp7a1, an LXR-responsive gene, was increased, suggesting increased LXR activity. Expression of mRNA encoding fatty acid translocase and ATP-binding cassette subfamily DALD member 3 was also increased in livers of corpulent JCR rats, indicating a potential role for these fatty acid transporters in the pathogenesis of disordered lipid metabolism in obesity. This study clearly demonstrates that substitution of dietary polyunsaturated fatty acid for carbohydrate in the corpulent JCR:LA-cp rat reduces de novo lipogenesis, at least in part, by reducing hepatic expression of SREBP-1c and that strategies directed toward reducing SREBP-1c expression in the liver may mitigate the adverse effects of hyperinsulinemia on hepatic lipid production.

The Use of Transcriptomics to Unveil the Role of Nutrients in Mammalian Liver

“…In this way, substitution of dietary monounsaturated or polyunsaturated fatty acid (olive oil and menhaden oil) for carbohydrate reduced hepatic expression of SREBP-1c, with concomitant reductions in hepatic triglyceride content, lipogenesis, and expression of enzymes related to lipid synthesis in corpulent James C. Russell (JCR:LA-cp) rats. Unexpectedly, this substitution increased expression of many peroxisomal proliferator-activated receptor-dependent enzymes mediating fatty acid oxidation [61]. Olive substitution for butter (10% of total energy) for two weeks modulated several genes related to lipolysis or lipogenesis in normal rats [62] and newly identified genes from other metabolisms ( Fsp27 and Syt1 ) in apoE-deficient mice [65].…”

“…Induction of SREBP-1c by insulin was dependent on LXR α . Expression of mRNA encoding fatty acid translocase and ATP-binding cassette subfamily DALD member 3 was also increased in livers of corpulent JCR rats, indicating a potential role for these fatty acid transporters in the pathogenesis of disordered lipid metabolism in obesity [61]. …”

“…The n-3 polyunsaturated fatty acid containing diets, provided as fish oil, regulated lipolytic and lipogenic gene expression and the tissue specificity of this regulation in mice [63], rats [62], and in JCR:LA-cp rats [61]. These diets also increased bile and cholesterol excretion controlling cholesterol metabolism by inducing cholesterol 7alpha-hydroxylase and its upstream transcription factors: D-site binding protein and liver X receptor-alpha in mice [97], and independently of LXR transcription in JCR:LA-cp rats [61]. These fatty acids regulated the expression of genes involved in many other pathways such as oxidative stress response and antioxidant capacity, cell proliferation, cell growth and apoptosis, cell signaling, and cell transduction.…”

Hepatic lipid accumulation is ameliorated in obese KK mice by dietary sei whale oil

“…Hepatic lipid levels and liver lipid metabolism-related gene expression were affected by the WO and FO diets, but the effects were more marked in the latter case. In previous studies it was demonstrated that oleic acid inhibits fatty acid synthesis-related gene expression and enhances PPARα target gene expression in the liver [31][32][33]. In the experimental diets used in this study, the oleic acid content was higher in the FO diet than in the WO diet (Table 2).…”

Gene expression changes in subcutaneous adipose tissue due to Cushing's disease

“…Muscle wasting is a well recognized adverse event of excess glucocorticoids caused by both increased muscle proteolysis and decreased protein synthesis (Deng et al 2004, Menconi et al 2007. Exposure of rats to glucocorticoids activates the muscle ubiquitin-proteasome system (Wing & Goldberg 1993, Price et al 1994, increasing muscle expression of proteases (cathepsins B and D, calpain) and components of the ubiquitin-proteasome pathway (Dardevet et al 1995) along with the inhibition of muscle protein synthesis (Long et al 2001).…”