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Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9983-8. doi: 10.1073/pnas.1314939111. Epub 2014 Jun 24.

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

Author information

1
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China;
2
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
3
Department of Radiology and Biomedical Imaging, School of Medicine, University of California, San Francisco, CA 94143-2520;
4
Department of Physiology, School of Medicine, University of California, San Francisco, CA 94143-2240;
5
Department of Cellular and Molecular Pharmacology, School of Medicine, University of California, San Francisco, CA 94158-2280; and.
6
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;Institute for Human Genetics, University of California, San Francisco, CA 94143 kathy.giacomini@ucsf.edu.

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.

KEYWORDS:

diabetes; fatty liver disease; vitamin B1

PMID:
24961373
PMCID:
PMC4103324
DOI:
10.1073/pnas.1314939111
[Indexed for MEDLINE]
Free PMC Article

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