Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biochemistry & Molecular Biophysics

First Advisor

Morris J. Birnbaum

Second Advisor

Mark Lemmon

Abstract

Diabetes is accompanied by dysregulation of glucose, lipid, and protein metabolism. In recent years, much effort has been spent on understanding how insulin regulates glucose and lipid metabolism, while the effect of insulin on protein metabolism has received less attention. In diabetes, hepatic production of serum albumin decreases, and it has long been established that insulin positively controls albumin gene expression. Yet, the detailed pathway via which insulin exerts this effect has not been described. In this study, we used a genetic approach in mice to identify the mechanism by which insulin regulates albumin production, both transcriptionally and post-transcriptionally. Albumin expression was significantly decreased in livers with insulin signaling disrupted by ablation of insulin receptor or Akt. Concomitant deletion of Forkhead Box O1 (Foxo1) in these livers rescued the decreased albumin secretion. Furthermore, expressing a constitutively active Foxo1 in the liver is sufficient to suppress albumin expression. Mammalian Target of Rapamacin Complex 1 (mTORC1) activity had a minor contribution to serum albumin production. Hepatic autophagy also played a minor role and contributed to albumin production post-transcriptionally in the absence of insulin signaling. In addition, we show that constitutive activation of Foxo1 is correlated with decreased occupancy of CCAAT/Enhancer Binding Protein α (C/EBPα) at the albumin promoter. These results demonstrate that serum albumin production is regulated mainly on the transcription level, and insulin stimulates albumin expression by inhibiting Foxo1, which acts as a gene repressor of albumin by directly or indirectly interfering with C/EBPα binding to the albumin promoter.

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