Enhancement in liver SREBP-1c/PPAR-α ratio and steatosis in obese patients: correlations with insulin resistance and long-chain polyunsaturated fatty acid depletion

Paulina Pettinelli (1) , Talía del Pozo (2) , Julia Araya (1) , Ramón Rodrigo (1) , A. Verónica Araya (3) , Gladys Smok (4) , Attila Csendes (5) , Luis Gutierrez (1) , Jorge Romero Rojas (1) , Owen Korn (1) , Fernando Maluenda (1) , Juan C. Diaz (1) , Guillermo Rencoret (1) , Italo Braghetto (1) , Jaime Castillo (1) , Jaime Poniachik (6) , Luis A. Videla (1)

1 Faculty of Medicine
2 UCHILE - Universidad de Chile = University of Chile [Santiago]
3 Department of Endocrinology
4 Department of Pathological Anatomy
5 Department of Surgery
6 Department of Medicine

Sterol receptor element binding protein-1c (SREBP-1c) and peroxisome proliferator activated receptor-α (PPAR-α) mRNA expression was assessed in liver as signaling mechanisms associated with steatosis in obese patients. Liver SREBP-1c and PPAR-α mRNA (RT-PCR), fatty acid synthase (FAS) and carnitine palmitoyltransferase-1a (CPT-1a) mRNA (real-time RT-PCR), and long-chain polyunsaturated fatty acid (LCPUFA)(GLC) contents, plasma adiponectin levels (RIA), and insulin resistance (IR) evolution (HOMA) were evaluated in 11 obese patients who underwent subtotal gastrectomy with gastro-jejunal anastomosis in Roux-en-Y and 8 non-obese subjects who underwent laparoscopic cholecystectomy (controls). Liver SREBP-1c and FAS mRNA levels were 33% and 70% higher than control values (P<0.05), respectively, whereas those of PPAR-α and CPT-1a were 16% and 65% lower (P<0.05), respectively, with a significant 62% enhancement in the SREBP-1c/PPAR-α ratio. Liver LCPUFA levels were 53% lower in obese patients who also showed IR and hipoadiponectinemia over controls (P<0.05). IR negatively correlated with both the hepatic content of LCPUFA (r=-0.55; P<0.01) and the plasma levels of adiponectin (r=-0.62; P<0.005). Liver SREBP-1c/PPAR-α ratio and LCPUFA showed a negative correlation (r=-0.48; P<0.02) and positive associations with either HOMA (r=0.75; P<0.0001) or serum insulin levels (r=0.69; P<0.001). In conclusion, liver up-regulation of SREBP-1c and down-regulation of PPAR-α occur in obese patients, with enhancement in the SREBP-1c/PPAR-α ratio associated with LCPUFA depletion and IR, a condition that may favour lipogenesis over FA oxidation thereby leading to steatosis.

Mots clés: Obesity; Liver steatosis; Sterol receptor element binding protein-1c; Peroxisome proliferator activated receptor-α; Insulin resistance

Paulina Pettinelli, Talía del Pozo, Julia Araya, Ramón Rodrigo, A. Verónica Araya, et al.. Enhancement in liver SREBP-1c/PPAR-α ratio and steatosis in obese patients: correlations with insulin resistance and long-chain polyunsaturated fatty acid depletion. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2009, 1792 (11), pp.1080. ⟨10.1016/j.bbadis.2009.08.015⟩. ⟨hal-00562931⟩