OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin

Ligong Chen(University of California, San Francisco), Yan Shu(University of California, San Francisco), Xiaomin Liang(University of California, San Francisco), Eugene C. Chen(University of California, San Francisco), Sook Wah Yee(University of California, San Francisco), Arik A. Zur(University of California, San Francisco), Shuanglian Li(University of California, San Francisco), Lu Xu(University of California, San Francisco), Kayvan R. Keshari(University of California, San Francisco), Michael J. Lin(University of California, San Francisco), Huan‐Chieh Chien(University of California, San Francisco), Youcai Zhang(University of California, San Francisco), Kari M. Morrissey(University of California, San Francisco), Jason Liu(University of California, San Francisco), J.M. Ostrem(University of California, San Francisco), Noah Younger(University of California, San Francisco), John Kurhanewicz(University of California, San Francisco), Kevan M. Shokat(University of California, San Francisco), Kaveh Ashrafi(University of California, San Francisco), Kathleen M. Giacomini(University of California, San Francisco)
Proceedings of the National Academy of Sciences
June 24, 2014
10.1073/pnas.1314939111
Cited by 236Open Access
Full Text

Abstract

Organic cation transporter 1, OCT1 (SLC22A1), is the major hepatic uptake transporter for metformin, the most prescribed antidiabetic drug. However, its endogenous role is poorly understood. Here we show that similar to metformin treatment, loss of Oct1 caused an increase in the ratio of AMP to ATP, activated the energy sensor AMP-activated kinase (AMPK), and substantially reduced triglyceride (TG) levels in livers from healthy and leptin-deficient mice. Conversely, livers of human OCT1 transgenic mice fed high-fat diets were enlarged with high TG levels. Metabolomic and isotopic uptake methods identified thiamine as a principal endogenous substrate of OCT1. Thiamine deficiency enhanced the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase. Metformin and the biguanide analog, phenformin, competitively inhibited OCT1-mediated thiamine uptake. Acute administration of metformin to wild-type mice reduced intestinal accumulation of thiamine. These findings suggest that OCT1 plays a role in hepatic steatosis through modulation of energy status. The studies implicate OCT1 as well as metformin in thiamine disposition, suggesting an intriguing and parallel mechanism for metformin and its major hepatic transporter in metabolic function.

Related Papers

No related papers found

Powered by citation graph analysis