The Role of Amino Acid Transport in the Regulation of mTORC1 by Metformin
The antihyperglycaemic drug metformin has become the most widely prescribed drug treatment for the management of type 2 diabetes mellitus. Despite being prescribed for over 50 years, the precise molecular mechanisms underlying metformin’s therapeutic effects remain poorly understood. Newly recognised health benefits of metformin, irrespective of diabetes status, have led to proposals of ‘re-purposing’ metformin for treatment of cancer, cardiovascular disease and ageing; conditions regularly associated with impaired regulation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) but not safely treatable with its inhibitor, rapamycin. Here we report that in the liver, the primary target tissue of metformin, metformin regulates mTORC1 signalling by inhibiting its activation by amino acids in an AMPK-independent manner. Furthermore, we present evidence to suggest that this occurs through a reversible mechanism ‘upstream’ of the amino acid sensor involving inhibition of hepatic uptake of leucine, a potent stimulator of mTORC1 activity. Using gene expression studies, we identified a role for metformin in decoupling uptake of small and large neutral amino acids, such as glutamine and leucine, from a favourable sodium gradient, involving significant reduction in mRNA expression of SNAT2. Consistent with impaired hepatic uptake and removal from the plasma, elevations in plasma concentrations of branched chain amino acids (BCAAs) and glutamine were observed in non-diabetic humans with chronic heart failure (CHF) receiving metformin. Furthermore, elevated plasma concentrations of leucine were significantly associated with improved plasma glucose and fasting insulin resistance index parameter (FIRI). Taken together, these results suggest a role for metformin in controlling mTORC1 via amino acid transport, akin to hepatic protein restriction. This study highlights the potential for ‘re-purposing’ metformin for use as a protein restriction mimetic in treatment of age-related diseases including cardiovascular disease, cancer and diabetes.
Networked Digital Library of Theses and Dissertations