Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content.

Xiaomin Liang,Kathleen M Giacomini,Qi Luo,Janna Abad,Ling Zou,Ligong Chen,Eugene C Chen,Meiling Piao,Huan-Chieh Chien,Arias Mifune,Frode Norheim,Sook Wah Yee,Meredith E Calvert,Sarah King,Ronald M Krauss,Nicole Soranzo

doi:10.1371/journal.pbio.2002907

Abstract

A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease and diabetes. Analysis of data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms in the organic cation transporter, OCT1 (SLC22A1), are significantly associated with higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and an increased risk for type 2 diabetes mellitus, yet the mechanism linking OCT1 to these metabolic traits remains puzzling. Here, we show that OCT1, widely characterized as a drug transporter, plays a key role in modulating hepatic glucose and lipid metabolism, potentially by mediating thiamine (vitamin B1) uptake and hence its levels in the liver. Deletion of Oct1 in mice resulted in reduced activity of thiamine-dependent enzymes, including pyruvate dehydrogenase (PDH), which disrupted the hepatic glucose–fatty acid cycle and shifted the source of energy production from glucose to fatty acids, leading to a reduction in glucose utilization, increased gluconeogenesis, and altered lipid metabolism. In turn, these effects resulted in increased total body adiposity and systemic levels of glucose and lipids. Importantly, wild-type mice on thiamine deficient diets (TDs) exhibited impaired glucose metabolism that phenocopied Oct1 deficient mice. Collectively, our study reveals a critical role of hepatic thiamine deficiency through OCT1 deficiency in promoting the metabolic inflexibility that leads to the pathogenesis of cardiometabolic disease.

Highlights

Hepatic energy metabolism is a major determinant of systemic glucose and lipid levels as well as total body adiposity, which in turn are key risk factors for cardiovascular and metabolic diseases [1, 2]
The Genome-wide association studies (GWAS) Catalog, database of Genotypes and Phenotypes Association Results Browser, and Genome-Wide Repository of Associations Between single nucleotide polymorphisms (SNPs) and Phenotypes (GRASP) identified two major phenotypes that were associated with genetic variants in SLC22A1 (OCT1) (Fig 1 and S1A and S1B Fig)
Through extensive characterization of Oct1 knockout mice, our data provide compelling evidence that Oct1 deficiency leads to a constellation of diverse effects on energy metabolism that are consistent with GWAS demonstrating strong associations between OCT1 polymorphisms and a variety of metabolic traits in humans (Fig 1 and Table 1)

Summary

Introduction

Hepatic energy metabolism is a major determinant of systemic glucose and lipid levels as well as total body adiposity, which in turn are key risk factors for cardiovascular and metabolic diseases [1, 2]. Genome-wide association studies (GWAS) have provided a wealth of information on the genes and pathways involved in hepatic energy metabolism, including apolipoprotein E (APOE), proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein receptor (LDLR) [3,4,5]. The mechanisms responsible for the genome-wide–level significant association of SLC22A1 (encoding the organic cation transporter, OCT1) with total and low-density lipoprotein (LDL) cholesterol [3] remains unexplored. Reduced-function polymorphisms of OCT1 have been associated with changes in the pharmacokinetics and pharmacodynamics of several drugs, including the opiate receptor agonist, morphine, and the anti-diabetic drug, metformin [10,11,12]. GWAS and fine mapping analysis showed that OCT1 functional variants are associated with acylcarnitine levels through efflux mechanism [13]

Methods

Results

Conclusion