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Blocking Fructose Transport Prevents Fatty Liver Disease in Mouse Model

By BiotechDaily International staff writers
Posted on 17 Jun 2014
Image: The transporter GLUT8 (green) is in the outer membrane of liver cells. In mice, blocking GLUT8 stops fructose from entering the liver and protects against nonalcoholic fatty liver disease. The liver cell nuclei are shown in blue (Photo courtesy of Dr. Brian J. DeBosch, Washington University School of Medicine).
Image: The transporter GLUT8 (green) is in the outer membrane of liver cells. In mice, blocking GLUT8 stops fructose from entering the liver and protects against nonalcoholic fatty liver disease. The liver cell nuclei are shown in blue (Photo courtesy of Dr. Brian J. DeBosch, Washington University School of Medicine).
A recent paper showed that blocking the action of the facilitative glucose and fructose transporter enzyme GLUT8 (Slc2A8 or solute carrier family 2 (facilitated glucose transporter) member 8) could prevent nonalcoholic fatty liver disease (NAFLD) in cultured mouse liver tissues.

NAFLD is one of the world's most common liver diseases, and it is considered to be the hepatic manifestation of the metabolic syndrome, which is characterized by obesity, elevated blood sugar, and high blood pressure.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) have been concentrating on the molecular factors regulating fructose transport, since excess dietary fructose causes both metabolic syndrome and NAFLD in rodents and humans. They previously demonstrated that female mice lacking GLUT8 exhibited impaired first-pass hepatic fructose metabolism, suggesting that fructose transport into the hepatocyte, the primary site of fructose metabolism, was in part mediated by GLUT8. In the current study, they tested the hypothesis that GLUT8 was required for hepatocyte fructose uptake and for the development of fructose-induced NAFLD.

The investigators reported in the April 18, 2014, issue of the Journal of Biological Chemistry that GLUT8 was a cell surface-localized transporter and that GLUT8 overexpression or GLUT8 siRNA-mediated gene silencing significantly induced and blocked radiolabeled fructose uptake in cultured hepatocytes. Furthermore, they presented evidence confirming diminished fructose uptake and de novo lipid synthesis in fructose-challenged GLUT8-deficient hepatocytes. Finally, livers from long term high-fructose diet-fed GLUT8-deficient mice were found to exhibit attenuated fructose-induced hepatic triglyceride and cholesterol accumulation without changes in hepatocyte insulin-stimulated Akt phosphorylation. Akt, also known as protein kinase B, is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. GLUT8 was thus essential for hepatocyte fructose transport and fructose-induced accumulation of fats in the liver.

“We showed that GLUT8 is required for fructose to get into the liver,” said first author Dr. Brian J. DeBosch, clinical fellow in pediatric gastroenterology at Washington University School of Medicine. “If you take away or block this transporter in mice, they no longer get diet-induced fatty liver disease.”

“Fatty liver disease is a major topic of research right now,” said Dr. DeBosch. “There are competing hypotheses about the origins of metabolic syndrome. One of these hypotheses is that insulin resistance begins to develop in the liver first. The thought is if we can prevent the liver from becoming unhealthy to begin with, maybe we can block the entire process from moving forward.”

Related Links:

Washington University School of Medicine



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