Dietary induced fatty liver disease is associated with downregulation of the liver abundance of stearoyl-CoA desaturase 1 (Scd1) mRNA and impaired liver protein dimerization independently of insulin resistance.

SOOKOIAN S; FERNÁNDEZ GIANOTTI T; BURGUEÑO A; PIROLA CJ

San Francisco

Congreso; 62nd Annual Meeting of American Association for the Study of Liver Diseases; 2011

American Association for the Study of Liver Diseases

Scd1 has recently gained much interest as a therapeutic target for obesity, insulin resistance (IR) and cardiovascular disease (CVD). Despite is well known that desaturases are highly regulated at transcriptional level by fatty acids, there is still inconsistent data about modulation of Scd1 expression in NAFLD. We evaluated whether modulation of Scd1 by dietary factors is modified by IR and explored the potential mechanisms associated with hepatic Scd1 regulation. Methods: we measured liver Scd1 mRNA abundance and protein levels in two experimental models of high fat diet (HFD)-induced NAFLD: Sprague Dawley (SD) rats with increased visceral fat and obesity and the spontaneously hypertensive rat (SHR) and its normotensive, insulin-sensitive control Wistar-Kyoto (WKY) strain, a rat model of metabolic syndrome and CVD. This strategy allows us to explore liver Scd1 in different metabolic environments. Adult rats were given standard chow diet (controls: CON, n=7) or HFD (n=7) for 10 weeks. Real-time and western blot were performed for assessment of mRNA and protein expression, respectively. Results: HFD-fed rats developed NAFLD in both strains; HFD-SHR rats were insulin resistant. Liver abundance of Scd1 mRNA was significantly downregulated in HFD rats, regardless of the strain: CON-SD: 235±195 vs. HFD-SD 4.5±2.9, (mean±SE), p<0.0004 and CON-SHR: 75.6±10.8, HFD-SHR: 4.48±17.4, CON-WKY: 168.7±17.4, HFD-WKY: 12.9±17.4, p<0.000001 (ANCOVA adjusted by HOMA); SHR rats showed significantly lower Scd1 mRNA compared to WKY (p<0.003). Analysis of liver Scd1 protein expression showed a particular pattern in the HFD groups, characterized by the presence of a higher level of a monomeric band of 33 KDa (p<0.003) and a decreased level of a dimeric band (66 Kda) (p<0.02) regardless of the strain. The monomer/dimer ratio was significantly (p<0.0002) higher in HFD rats (HFD-SHR: 1.9 vs CON-SHR: 0.55 and HFD-WKY: 2.1 vs CON-WKY: 0.9). SHR rats showed decreased total Scd1 protein levels than WKY rats (p<0.02). In summary, HFD is associated with a decreased level of Scd1 transcript and lost of liver Scd1 protein dimerization, which may directly impact on protein function and activity. These data suggest that Scd1 is a critical enzyme in controlling liver lipid overloading and is highly regulated by dietary factors even in the absence of IR. The CV phenotype per se may also affect liver Scd1 behavior. The understanding of the mechanisms behind liver Scd1 regulation may influence decisions about the use of therapeutic interventions that activate (i.e. thiazolidinediones or glitazones) instead of inhibiting Scd1 and strongly support dietary intervention for NAFLD patients.