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Abcb4 – A modulator of glucose homeostasis?

The glucose metabolism is regulated by various factors and influences. It depends – among other regulatory influences – on the production of bile. Bile is composed mainly of water, sterols, bile salts, and phospholipids, in particular, phosphatidylcholine (PC). These substances, apart from water, are transported from hepatocytes into bile by specific hepatobiliary ATP-binding cassette (ABC) proteins, namely ABCB4 (PC floppase), ABCB11 (bile salt export pump), and ABCG5/8 (sterol transporter). Once transferred into the lumen of bile ducts, sterols, bile salts, and PC form mixed micelles to reduce the toxicity of bile acids and to establish physiological bile flow. Conversely, in the case of dysfunction of the ABC proteins, bile composition is deranged and cholestatic disorders with liver dysfunction prevail.

The scientists around Katrin Hochrath and Frank Lammert analysed Abcb4 deficient mice (Abcb4-/-). Mice lacking the ABCB4 transporter are characterized by the absence of PC in bile. As a result, ABCB4-deficient animals spontaneously develop chronic cholangitis and secondary biliary fibrosis, resembling sclerosing cholangitis in humans.

The Abcb4-/- mice were systematically phenotyped in the German Mouse Clinic. In the Clinical Chemistry Screen several blood parameters were found to be changed, indicating mixed hepatocellular and cholestatic liver injury. In detail, serum activities of alkaline phosphatase (AP) and bilirubin levels were increased as well as levels of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH).

After overnight fasting Abcb4-/- mice showed significantly higher blood glucose concentrations than wild-type controls. If mice had access to food overnight Abcb4-/- mice displayed significantly lower plasma glucose concentrations. Knockout mice presented with lower glucose peaks in intraperitoneal glucose tolerance test. Based on the glucose concentrations at different time points the calculated area under the curve values of Abcb4-/- animals are significantly lower between 30 and 120 minutes after glucose administration. The Molecular Phenotyping Screen identified regulated genes that were previously identified as modifiers of chronic liver inflammation and fibrosis. Among these are cathepsin B (Ctsb), carbamoyl-phosphate synthetase 1 (Cps1), hemolytic complement factor 5 (Hc), decorin (Dcn), glycine N-methyltransferase (Gnmt) and lipocalin 2 (Lcn2). In addition, 11 genes involved in carbohydrate metabolism were identified.

In order to find out if ABCB4 is also relevant for carbohydrate metabolism in humans, the scientists around Hochrath and Lammert genotyped four common ABCB4 variants in patients. These variants have previously been shown to be associated with hepatic phenotypes. Carriers of specific ABCB4c.711 variants displayed significantly different serum glucose levels. The homozygous carriers of the procholeastic genotype presented significantly lower median glucose levels than carriers of the other variants.

The results propose that ABCB4 might play a critical role in glucose homeostasis in mice and humans.

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis, Katrin Hochrath et al., The FASEB Journal article fj.12-209379. Published online October 1, 2012.