Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase

Joshua L. Owen, Yuanyuan Zhang, Soo Han Bae, Midhat S. Farooqi, Guosheng Liang, Robert E Hammer, Joseph L Goldstein, Michael S Brown

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

Insulin activates sterol regulatory element-binding protein-1c (SREBP-1c) in liver, thereby increasing fatty acid and triglyceride synthesis. We created a line of transgenic rats that produce epitope-tagged human SREBP-1c in liver under control of the constitutive apolipoprotein E promoter/enhancer. This systemallows us to dissect the pathway by which insulin stimulates SREBP-1c processing without interference by the insulin-mediated increase in SREBP-1c mRNA. Rats are used because freshly isolated rat hepatocytes respond much more robustly to insulin than domouse hepatocytes. The data reveal that insulin-mediated stimulation of SREBP-1c processing requires the mechanistic target of rapamycin complex 1 (mTORC1), which also is required for insulin-mediated SREBP-1cmRNA induction. However, in contrast to mRNA induction, insulin stimulation of SREBP-1c processing is blocked by an inhibitor of p70 S6-kinase. The data indicate that the pathways for insulin enhancement of SREBP-1c mRNA and proteolytic processing diverge after mTORC1. Stimulation of processing requires the mTORC1 target p70 S6-kinase, whereas induction of mRNA bypasses this enzyme. Insulin stimulation of both processes is blocked by glucagon. The transgenic rat system will be useful in further defining the molecular mechanism for insulin stimulation of lipid synthesis in liver in normal and diabetic states.

Original languageEnglish (US)
Pages (from-to)16184-16189
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number40
DOIs
StatePublished - Oct 2 2012

Keywords

  • Lipid metabolism
  • mTORC1 kinase

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase'. Together they form a unique fingerprint.

Cite this