The role of mammalian target of rapamycin complex 1 in hepatic physiology and disease

The multi-component kinase mTOR complex 1 (mTORC 1) coordinates nutrient and growth factor inputs with numerous downstream processes including protein translation, autophagy, metabolism and cell growth. We have found that inhibition of mTORC 1 with rapamycin treatment suppressed whole-body postnatal growth similar to reduced caloric intake. We found that while feeding activated mTORC 1 in almost every tissue, there was variability in the upstream activating stimuli. The role of mTORCl in organ growth was further elucidated by studies we performed using liver-specific mTORC1 gain and loss of function mutants. Confirming our studies with rapamycin, genetic activation or suppression of mTORC 1 increased and decreased liver size respectively, and rendered the liver insensitive to nutrients. Rendering the liver insensitive to nutrients also had functional consequences. In response to starvation, the liver shifts to fatty acid catabolism and generates ketone bodies to supplement lowered glucose levels. We find that constitutive activation of mTORC1 prevents the liver from initiating fatty-acid oxidation and ketone production in response to fasting. Many aspects of the hepatic fasting response malfunction in old age including fatty acid catabolism and ketogenesis. We find this aging-dependent process is mediated by mTORC 1, and thus loss of mTORC 1 function throughout the adult life of the animal prevents the aging induced decrease in hepatic ketogenesis. As such, pharmaceutical inhibition of mTORC 1 may be beneficial in battling metabolic disorders due to aging.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2010

Author dc:creator

• Sengupta, Shomit

Advisor dc:contributor.advisor

• David M. Sabatini.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/57673

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/57673