Dysregulation of sterol regulatory element binding protein–1c in livers of morbidly obese women is associated with altered suppressor of cytokine signaling–3 and signal transducer and activator of transcription–1 signaling

We compared hepatic expression of genes that regulate lipid biosynthesis and metabolic signaling in liver biopsy specimens from women who were undergoing gastric bypass surgery (GBP) for morbid obesity (MO) to that in women undergoing ventral hernia repair who had experienced massive weight loss (MWL) following prior GBP. Comprehensive metabolic profiles of MO (22 subjects) and MWL (9 subjects) were also compared. Analyses of gene expression in liver biopsies from MO and MWL were accomplished by Affymetrix microarray, real-time PCR and Western blotting techniques. Following GBP, MWL subjects had lost on average 102 pounds as compared to MO subjects. This was accompanied by effective reversal of the dyslipidemia and insulin resistance that was present in MO. As compared with MWL, livers of MO subjects exhibited increased expression of Sterol Regulatory Element Binding Protein (SREBP-1c) and its downstream lipogenic targets, fatty acid synthase (FAS) and acetyl-CoA-carboxylase-1 (ACC-1). Livers of MO subjects also exhibited enhanced expression of suppressor of cytokine signaling -3 (SOCS-3) protein and attenuated Janus kinase signal transducer and activator of transcription (JAK/STAT) signaling. Consistent with these findings, we found that the human SREBP-1c promoter was positively regulated by insulin and negatively regulated by STAT3. These data support the hypothesis that SOCS-3 mediated attenuation of the STAT signaling pathway and resulting enhanced expression of SREBP-1c, a key regulator of de novo lipid biosynthesis, are mechanistically related to the development of hepatic insulin resistance and dyslipidemia in morbidly obese women.