title: OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin.
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.
authors: 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;
authors: Ligong
authors: L
authors: Chen
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Yan
authors: Y
authors: Shu
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Xiaomin
authors: X
authors: Liang
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Eugene C
authors: EC
authors: Chen
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Sook Wah
authors: SW
authors: Yee
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Arik A
authors: AA
authors: Zur
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Shuanglian
authors: S
authors: Li
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Lu
authors: L
authors: Xu
authors: Department of Radiology and Biomedical Imaging, School of Medicine, University of California, San Francisco, CA 94143-2520;
authors: Kayvan R
authors: KR
authors: Keshari
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Michael J
authors: MJ
authors: Lin
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Huan-Chieh
authors: HC
authors: Chien
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Youcai
authors: Y
authors: Zhang
authors: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-2911;
authors: Kari M
authors: KM
authors: Morrissey
authors: Department of Physiology, School of Medicine, University of California, San Francisco, CA 94143-2240;
authors: Jason
authors: J
authors: Liu
authors: Department of Cellular and Molecular Pharmacology, School of Medicine, University of California, San Francisco, CA 94158-2280; and.
authors: Jonathan
authors: J
authors: Ostrem
authors: Department of Cellular and Molecular Pharmacology, School of Medicine, University of California, San Francisco, CA 94158-2280; and.
authors: Noah S
authors: NS
authors: Younger
authors: Department of Radiology and Biomedical Imaging, School of Medicine, University of California, San Francisco, CA 94143-2520;
authors: John
authors: J
authors: Kurhanewicz
authors: Department of Cellular and Molecular Pharmacology, School of Medicine, University of California, San Francisco, CA 94158-2280; and.
authors: Kevan M
authors: KM
authors: Shokat
authors: Department of Physiology, School of Medicine, University of California, San Francisco, CA 94143-2240;
authors: Kaveh
authors: K
authors: Ashrafi
authors: 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.
authors: Kathleen M
authors: KM
authors: Giacomini
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005234:Fatty Liver / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D050811:Octamer Transcription Factor-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D013831:Thiamine / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D050811:Octamer Transcription Factor-1; C494166:Pou2f1 protein, mouse; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D013831:Thiamine
keywords: diabetes; fatty liver disease; vitamin B1