An analbuminemic colony was established from Sprague-Dawley rats. Analbuminemia was inherited as an autosomal recessive trait. The rates of growth and reproduction of the mutant rats were no different from those of normal rats. Biochemically, the mutant was characterized by an extraordinarily low serum albumin content and a hyperlipidemia. Total serum protein in the mutant rat was similar to that of control Sprague-Dawley rats, with increased globulin. Serum cholesterol was inversely correlated with a decrease in albumin; the correlation coefficient for ablumin was --.92. These mutant rats may serve as a model of human familial analbuminemia and may also be useful in elucidating the functional roles of albumin.

The Shumiya cataract rat (SCR) is a hereditary cataractous strain. It is thought that the continuous occurrence of poorly differentiated epithelial cells at the bow area of the lens forms the pathophysiological basis for cataract formation in SCRs. In this study, we attempted to identify the genes associated with cataract formation in SCRs by positional cloning. Genetic linkage analysis revealed the presence of a major cataract locus on chromosome 20 as well as a locus on chromosome 15 that partially suppressed cataract onset. Hypomorphic mutations were identified in genes for lanosterol synthase (Lss) on chromosome 20 and farnesyl diphosphate farnesyl transferase 1 (Fdft1) on chromosome 15, both of which function in the cholesterol biosynthesis pathway. A null mutation for Lss was also identified. Cataract onset was associated with the specific combination of Lss and Fdft1 mutant alleles that decreased cholesterol levels in cataractous lenses to about 57% of normal. Thus, cholesterol insufficiency may underlie the deficient proliferation of lens epithelial cells in SCRs, which results in the loss of homeostatic epithelial cell control of the underlying fiber cells and eventually leads to cataractogenesis. These findings may have some relevance to other types of cataracts, inborn defects of cholesterol synthesis, and the effects of cholesterol-lowering medication.

No abstract

An albumin-deficient and jaundiced strain of rats (AJR) was established by crossing Nagase analbuminemic rats (NAR) with jaundiced Gunn rats. AJR have no serum albumin and die with kernicterus within 3 weeks after birth. Their serum bilirubin level was 25 per cent (20 micrograms/ml) of that of Gunn rats at 1-2 weeks of age, while their brain bilirubin content was 1.2-2.7 times (4-5 micrograms/g brain) that of Gunn rats. Binding of bilirubin to NAR plasma proteins was examined. The bilirubin binding protein in NAR plasma was found to be lipoprotein, showing an association constant of 6.7 X 10(6) M-1. Bilirubin-transport into the brain of postnatal NAR was investigated by intravenous infusion of bilirubin with taurocholate. The brain bilirubin level of NAR infused with free bilirubin was 1.6 times that of normal rats. In NAR, the brain level on infusion of lipoprotein-bound bilirubin was similar to that on infusion of free bilirubin, but albumin-bound bilirubin scarcely entered the brain. These findings suggest that lipoprotein-bound bilirubin can diffuse across the blood-brain barrier into the brain.

These findings strongly suggest that iNOS is involved in cataract formation in SCR. The induction of iNOS occurs prior to the elevation of calcium content and its induction is inhibited by AG-treatment. Considering our previous result that the elevation of calcium content is also prevented by AG-treatment, it is conceivable that upregulation of iNOS causes calcium influx into lens cells and the subsequent activation of calpain.