Exploring the Physiological Role of Transthyretin in Glucose Metabolism in the Liver.

Mobina Alemi,Sofia C Tavares,Pedro F Oliveira,José Ricardo Vieira,Ângela Oliveira,Marco G Alves,Isabel Cardoso

doi:10.3390/ijms22116073

Abstract

Transthyretin (TTR), a 55 kDa evolutionarily conserved protein, presents altered levels in several conditions, including malnutrition, inflammation, diabetes, and Alzheimer’s Disease. It has been shown that TTR is involved in several functions, such as insulin release from pancreatic β-cells, recovery of blood glucose and glucagon levels of the islets of Langerhans, food intake, and body weight. Here, the role of TTR in hepatic glucose metabolism was explored by studying the levels of glucose in mice with different TTR genetic backgrounds, namely with two copies of the TTR gene, TTR+/+; with only one copy, TTR+/−; and without TTR, TTR−/−. Results showed that TTR haploinsufficiency (TTR+/−) leads to higher glucose in both plasma and in primary hepatocyte culture media and lower expression of the influx glucose transporters, GLUT1, GLUT3, and GLUT4. Further, we showed that TTR haploinsufficiency decreases pyruvate kinase M type (PKM) levels in mice livers, by qRT-PCR, but it does not affect the hepatic production of the studied metabolites, as determined by 1H NMR. Finally, we demonstrated that TTR increases mitochondrial density in HepG2 cells and that TTR insufficiency triggers a higher degree of oxidative phosphorylation in the liver. Altogether, these results indicate that TTR contributes to the homeostasis of glucose by regulating the levels of glucose transporters and PKM enzyme and by protecting against mitochondrial oxidative stress.

Highlights

The liver, one of the largest organs in the human body, is able to eliminate most of the threats exposed by environmental contaminants, pharmaceuticals, and microorganisms [1] and store and produce energy, proteins, and lipids [2]
TTR deficiency in TTR−/− mice did not induce any alteration in glucose (192.16 ± 11.10 mg/dL), confirming previous reports [24], which may be explained by compensation mechanisms developed to overcome the total absence of TTR at all stages of development of these animals
In order to have an integrative view regarding the effect of TTR on glucose metabolism and the fate of consumed glucose in the liver (Figure 3A), we evaluated the expression of the pyruvate kinase M type (PKM) enzyme, responsible for converting phosphoenolpyruvate (PEP) to pyruvate during glycolysis

Summary

Introduction

The liver, one of the largest organs in the human body, is able to eliminate most of the threats exposed by environmental contaminants, pharmaceuticals, and microorganisms [1] and store and produce energy, proteins, and lipids [2]. Plasma glucose can be transported across the hepatocyte membrane through glucose transporters (GLUTs), stored as glycogen or consumed by glycolysis, followed by tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation, producing energy in the form of ATP. Hepatic glucose uptake and efflux are influenced by different mechanisms, namely glycolysis, gluconeogenesis, and expression of GLUTs. Importantly, insulin resistance, hyperlipidaemia, alcohol consumption, viral infection, carcinogenesis, and many other conditions can dysregulate these systems [10]. GLUT2 levels have been shown to be increased in insulin-deficient diabetes [12], obesity, and insulin resistance, which exacerbates metabolic dysfunction in non-alcoholic fatty liver disease [13]. High doses of glucose as reported in a streptozotocin diabetes mellitus model were shown to dysregulate GLUT1 protein expression or localization and demonstrated to be normalized by metformin [15]. It has been shown that GLUT3 translocates to the plasma membrane in response to insulin, and insulin-stimulated glucose uptake was abolished with siRNA-mediated GLUT3 knockdown [18]

Methods

Results

Conclusion