KK/Snk mice (previously KK/San) possessing a recessive mutation ( hypl ) of the angiopoietin-like 3 ( Angptl3 ) gene homozygously exhibit a marked reduction of VLDL due to the decreased Angptl3 expression. Recently, we proposed that Angptl3 is a new class of lipid metabolism modulator regulating VLDL triglyceride (TG) levels through the inhibition of lipoprotein lipase (LPL) activity. In this study, to elucidate the role of Angptl3 in atherogenesis, we investigated the effects of hypl mutation against hyperlipidemia and atherosclerosis in apolipoprotein E knockout (apoEKO) mice. ApoEKO mice with hypl mutation (apoEKO-hypl ) exhibited a significant reduction of VLDL TG, VLDL cholesterol, and plasma apoB levels compared with apoEKO mice. Hepatic VLDL TG secretion was comparable between both apoE-deficient mice. Turnover studies revealed that the clearance of both [ 3 H]TG-labeled and 125 I-labeled VLDL was significantly enhanced in apoEKO-hypl mice. Postprandial plasma TG levels also decreased in apoEKO-hypl mice. Both LPL and hepatic lipase activities in the postheparin plasma increased significantly in apoEKO-hypl mice, explaining the enhanced lipid metabolism. Furthermore, apoEKO-hypl mice developed 3-fold smaller atherogenic lesions in the aortic sinus compared with apoEKO mice. Taken together, the reduction of Angptl3 expression is protective against hyperlipidemia and atherosclerosis, even in the absence of apoE, owing to the enhanced catabolism and clearance of TG-rich lipoproteins. The accrued evidence that lipid-lowering therapy limits the progression of atherosclerosis and reduces the events of coronary artery diseases is overwhelming (1, 2). The focus has been on the reduction of LDL cholesterol (3, 4). Recent studies have also pointed out the importance of reducing triglyceride (TG)-rich lipoproteins such as chylomicrons, VLDL, and their remnants, and of raising HDL cholesterol (5, 6). In addition, postprandial hypertriglyceridemia is mentioned as an independent risk factor for atherogenesis (7,8).In a colony of KK mice with mild obesity, hyperlipidemia, and diabetes, we found mutant mice (KK/Snk, previously KK/San) that were characterized by a significant decrease in plasma lipid levels, mainly due to the reduction of TG-rich lipoproteins, despite their obesity and diabetes. Genetic studies for the mutation, named hypolipidemia ( hypl ), in KK/Snk mice identified a 4 bp nucleotide insertion in exon 6 of a gene encoding angiopoietin-like 3 ( Angptl3 ), which causes a premature stop codon after a frameshift (9). Angptl3 is a secretory protein of 70 kDa expressed predominantly in the liver, and has a signal sequence, coiled-coil domain, and fibrinogen-like domain similar to those of other angiopoietin families (10, 11). In KK/Snk mice with the homozygous hypl mutation, Angptl3 expression was markedly decreased, probably due to the instability of mutant mRNA, resulting in a hypolipidemic trait (9). In contrast, adenovirus-mediated overexpression of Angptl3 or intravenous injection of the purified...

Abstract:The cerebellar calcification (CC) rat is a new neurodegenerative mutant with severe Purkinje cell loss and symmetrical calcifications in the cerebellar cortex manifesting ataxia: lack of coordination in body movements. In the present study, histopathological features were examined in the Purkinje cell degeneration in postnatal homozygous suckling rats without clinical signs, which were genotyped by microsatellite markers. In addition, the calcified Purkinje cells were investigated ultrastructurally and elemental analysis was performed on the deposits. Body weight of the homozygous (cc/cc) rats was already slightly lower compared with the heterozygotes (cc/+) in the neonatal stage. The degeneration of the Purkinje cells in the cc/cc rats was recognized obviously in lobules VI, VII, VIII and IX from 14 days after birth, a few days before the appearance of the ataxic behavior. The Purkinje cells in the region along the fissure between the VIII and IX lobule areas were intensely positive for periodic acid-Schiff reaction specific to glycoconjugates, and in this region, calcium depositions were weakly positive for von Kossa's stain. Electron microscopy also revealed that the calcified Purkinje cells possessed numerous electrondense bodies containing inclusions with cystic structures such as vesicles, mitochondria and lysosomes, and these bodies were mainly composed of calcium and phosphorous. These findings suggest abnormal storage of glycoconjugates might be a trigger of Purkinje cell degeneration and serves as a matrix for accumulation of calcium phosphate in the cerebellum of CC rats.

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A new neurological mutant has been found in the inbred F344 strain of rats. The mutation is inherited as an autosomal recessive trait and is manifest clinically by a hesitant and wobbling gait with asynergic limbs and slight tremor. These symptoms begin at 16-18 days of age and remain essentially constant thereafter. Histologic examination revealed severe degeneration of the Purkinje cells and symmetrical calcification in these and in their dendritic branches in the cerebellar cortex. Such calcified Purkinje cells were intensely stained with the periodic acid-Schiff (PAS) method. PAS-positive substances in the Purkinje cells and extending diffusely over the lesioned sites in the molecular layer were also evident before calcification took place. We have named this neurological mutant the Cerebellar Calcification (CC) rat with the gene symbol cc. This offers a new animal model for the study of the Purkinje cell degeneration and intracranial calcification.

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