Insulin Stimulation of Sterol Regulatory Element-Binding Protein-1c Processing in Liver: Lessons from Transgenic Rats



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Transcriptional control of hepatic fatty acid (FA) and triglyceride (TG) synthesis is mediated by SREBP-1c, one of three sterol regulatory element-binding protein (SREBP) isoforms. SREBPs are endoplasmic reticulum (ER) membrane-bound transcription factors that require escort to the Golgi apparatus followed by proteolytic cleavage from the membrane. This process liberates the active transcription factor portion of SREBP to translocate to the nucleus to activate transcription of its target genes. SREBP-1c is unique among the SREBP isoforms since it is highly enriched in liver and is activated by insulin. Therefore the best cell culture model system to study SREBP-1c function is freshly isolated primary rat hepatocytes due to their tissue origin and insulin sensitivity (cultured mouse hepatocytes lose insulin responsiveness). Using this model, insulin has been shown to activate the transcription of SREBP-1c, requiring mechanistic target of rapamycin complex 1 (mTORC1), but not its downstream target, p70 ribosomal protein S6 kinase (S6K). Insulin has also been implicated in the activation of proteolytic processing of SREBP-1c, but previous attempts to study this process have been confounded by the concomitant increase in SREBP-1c mRNA and precursor protein when primary hepatocytes are treated with insulin. To circumvent this problem, transgenic rats were created that express epitope-tagged human SREBP-1c under control of the apolipoprotein E (apoE) promoter/enhancer, which imparts constitutive, liver-specific expression to the transgene. Since the expression of the transgene is not regulated by insulin, the effect of insulin on the processing of SREBP-1c per se can now be studied. When hepatocytes isolated from transgenic rats were treated with insulin, the amount of cleaved nuclear SREBP-1c rapidly increased. Insulin-induced processing of SREBP-1c required both mTORC1 and S6K. This indicated a bifurcation in the insulin signal downstream of mTORC1, with SREBP-1c processing requiring S6K and SREBP-1c transcription bypassing this requirement. These findings have implications for the role of insulin in the control of hepatic FA and TG synthesis through SREBP-1c. This is relevant in states of insulin resistance and Type 2 diabetes where abnormally high levels of insulin cause pathologic accumulation of FAs and TGs.

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