RESUMO
AIMS AND METHODS: We 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. RESULTS: HFD-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. CONCLUSION: Diet-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.
Assuntos
Fígado Gorduroso/enzimologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Resistência à Insulina/fisiologia , Estearoil-CoA Dessaturase/metabolismo , Análise de Variância , Animais , Western Blotting , Dieta Hiperlipídica/efeitos adversos , Dimerização , Ensaio de Imunoadsorção Enzimática , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não ParamétricasRESUMO
UNLABELLED: In this study, we contrasted the hypothesis that maternal diet during pregnancy has an impact on fetal metabolic programming through changes in liver mitochondrial DNA (mtDNA) content and transcriptional activity of Ppargc1a and that these effects are sex specific. METHODS: Rats were fed either high-fat (HFD) or standard chow diet (SCD) during gestation and lactation. The resulting adult male and female offspring were fed either HFD or SCD for an 18-week period, generating eight experimental groups. RESULTS: Maternal HFD feeding during pregnancy is associated with a decreased liver mtDNA copy number (P<.008). This effect was independent of the offspring sex or diet, and was significantly associated with fatty liver when dams were fed HFD (P<.05, adjusted by homeostasis model assessment of insulin resistance, HOMA-IR). We also found that maternal HFD feeding results in a male-specific significant reduction of the liver abundance of Ppargc1a mRNA (P<.004), which significantly impacted peripheral insulin resistance. Liver expression of Ppargc1a was inversely correlated with HOMA-IR (R=-0.53, P<.0003). Only male offspring exposed to a chronic metabolic insult in adult life were insulin resistant and hyperleptinemic, and showed abnormal liver and abdominal fat accumulation. Liver abundance of Tfam, Nrf1, Hnf4a, Pepck and Ppparg mRNA was not associated with maternal programming. In conclusion, maternal high-fat diet feeding during pregnancy programs liver mtDNA content and the transcriptional activity of Ppargc1a, which strongly modulates, in a sex-specific manner, glucose homeostasis and organ fat accumulation in adult life after exposure to a nutritional insult.