ATVB 2003

Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

Vincent W. Bloks*, Willie W. Bakker-van Waarde*, Henkjan J. Verkade, Ido Kema¹, Rick Havinga, Henk Wolters, Frank G. Schaap², Pieter J.J. Sauer, Edwin Vink², Albert K. Groen², and Folkert Kuipers

From the Center for Liver, Digestive and Metabolic Diseases, Laboratories of Pediatrics and of ¹Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, the Netherlands; and ²the AMC Liver Center, Academic Medical Center, Amsterdam, the Netherlands

 

Type I diabetes is associated with altered hepatic bile formation and increased intestinal cholesterol absorption.

The ATP Binding Cassette (ABC) halftransporters ABCG5 and ABCG8 have been implicated in control of both hepatobiliary cholesterol secretion and intestinal cholesterol absorption.

We have evaluated the expression of Abcg5 and Abcg8 in liver and intestine of rats with streptozotozin (STZ)-induced diabetes in relation to relevant metabolic parameters.

Real-time PCR analysis revealed that hepatic mRNA levels of both Abcg5 (-76%) and Abcg8 (-71%) were reduced in STZ-diabetic rats when compared to controls.

In spite of elevated levels of HDL cholesterol, considered a major source of biliary cholesterol, secretion of the sterol into bile relative to that of bile salts was reduced by 65% in diabetic animals.

Intestinal mRNA levels of Abcg5 (-47%) and Abcg8 (-43%) as well as Abcg5 protein levels were also reduced in insulin-deficient animals.

This was accompanied by a 3-fold increase in plasma b -sitosterol levels and by a doubling of the calculated apparent cholesterol absorption.

These effects partially normalized upon insulin supplementation.

Our data indicate that effects of insulin- deficiency on bile composition and cholesterol absorption in rats are, at least partly, attributable to changes in hepatic and intestinal Abcg5 and Abcg8 expression.

When similar events occur in human diabetics, as suggested by elevated plasma levels of plant sterols in subjects with poorly controlled type I diabetes, this may contribute to an enhanced risk for development of atherosclerosis.

Published ATVB2003, Abstractbook, P234, pag 62