Dysregulated hepatic expression of glucose transporters in chronic disease: contribution of semicarbazide-sensitive amine oxidase to hepatic glucose uptake

Abstract

Insulin resistance is common in patients with chronic liver disease (CLD). Serum levels of soluble vascular adhesion protein-1 (VAP-1) are also increased in these patients. The amine oxidase activity of VAP-1 stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. We aimed to document human hepatocellular expression of glucose transporters (GLUTs) and to determine if VAP-1 activity influences receptor expression and hepatic glucose uptake. Quantitative PCR and immunocytochemistry were used to study human liver tissue and cultured cells. We also used tissue slices from humans and VAP-1-deficient mice to assay glucose uptake and measure hepatocellular responses to stimulation. We report upregulation of GLUT1, -3, -5, -6, -7, -8, -9, -10, -11, -12, and -13 in CLD. VAP-1 expression and enzyme activity increased in disease, and provision of substrate to hepatic VAP-1 drives hepatic glucose uptake. This effect was sensitive to inhibition of VAP-1 and could be recapitulated by H2O2. VAP-1 activity also altered expression and subcellular localization of GLUT2, -4, -9, -10, and -13. Therefore, we show, for the first time, alterations in hepatocellular expression of glucose and fructose transporters in CLD and provide evidence that the semicarbazide-sensitive amine oxidase activity of VAP-1 modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease.

In vivo confirmation of altered hepatic glucose metabolism in patients with liver fibrosis/cirrhosis by 18F-FDG PET/CT

“…These findings are in accord with the morphological changes in the expression of GLUT in the liver parenchyma because hepatocytes are capable of gluconeogenesis and their need for glucose uptake is modest [ 41 ]. In normal liver parenchyma, all GLUTs are expressed, except for GLUT-7 [ 42 ], and the liver parenchyma shows overexpression of GLUT-2, − 8, − 9, and − 10 [ 43 ]. GLUT-1 and GLUT-2 allow for efficient uptake of glucose at low plasma glucose concentrations [ 44 ].…”

“…Expression of these transporters in liver cells is restricted to hepatocytes proximal to the hepatic venule [ 45 ]. In damaged liver parenchyma, the majority of GLUTs are upregulated compared to normal liver parenchyma [ 43 ] and the expression of GLUT-1 in hepatocytes is increased, while GLUT-2 is decreased [ 46 ]. While GLUT-2 ensures, independently of insulin, with its low affinity and high transport capacity, that intracellular and extracellular glucose concentrations are in equilibrium [ 47 ], GLUT-1 has a higher affinity for glucose and is nearly saturated under physiological conditions [ 48 ].…”

“…In addition, the amine oxidase activity of VAP-1 is upregulated in chronic liver diseases [ 49 ]. VAP-1 plays a significant role in glucose uptake into hepatocytes as it stimulates glucose uptake via translocation of transporters to the cell membrane [ 43 , 50 ]. In conclusion, the high affinity of GLUT-1 for glucose in combination with its increased expression in damaged liver parenchyma might explain the increased 18 F-FDG uptake we observed in patients with liver fibrosis suggesting a higher glucose uptake for liver cells.…”

Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease

“…A tight relationship exists between various chronic metabolic diseases, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD), all of them reaching epidemic dimensions on a global scale [258]. While NAFLD increases type 2 diabetes incidence and the occurrence of late complications, type Table 1 Overview of main GLUTs in the liver, muscle, and adipose tissue and their tissue-specific function in metabolism Tissue Isoform Tissue-specific function in metabolism Liver GLUT1 Postnatal development and organogenesis of the liver [89]; main glucose transporter in non-parenchymal cells, relatively low levels in hepatocytes [221]; elevated in non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD) [109], and hepatocellular carcinoma (HCC) [267]; reduced surface expression in hepatitis C virus (HCV) infection [111]; may contribute to glucotoxicity and oxidative stress [220] GLUT2 Most abundant GLUT isoform in hepatocytes, responsible for bulk of glucose uptake, but does not directly mediate hepatic glucose output [80]; involved as hepatoportal glucose sensor [20,21]; SLC2A2 deficiency causal for Fanconi-Bickel syndrome (FBS) [61,144]; gene variants have been associated with fasting hyperglycemia, transition to type 2 diabetes, hypercholesterolemia, and the risk of cardiovascular diseases [60]; downregulated in HCV infection [111] GLUT5 Fructose transport, dietary fructose consumption associated with increased expression, non-alcoholic fatty liver disease (NAFLD)…”

Genome‐wide scan for circulating vascular adhesion protein‐1 levels: MACROD2 as a potential transcriptional regulator of adipogenesis

“…Possible substrates of VAP‐1 include cell‐surface molecules containing free NH 2 groups. These endogenous amine substrates have been shown to exert insulin‐like actions in adipocytes. Deamination of these amines leads to hydrogen peroxide and aldehydes production.…”