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.
1 The aim of this study was to evaluate the potency of YM-53601 ((E)-2-[2-¯uoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a new inhibitor of squalene synthase, in reducing both plasma cholesterol and triglyceride levels, compared with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and ®brates, respectively. 2 YM-53601 equally inhibited squalene synthase activities in hepatic microsomes prepared from several animal species and also suppressed cholesterol biosynthesis in rats (ED 50 , 32 mg kg 71 ). 3 In guinea-pigs, YM-53601 and pravastatin reduced plasma nonHDL-C (=total cholesterol ± high density lipoprotein cholesterol) by 47% (P50.001) and 33% (P50.001), respectively (100 mg kg 71 , daily for 14 days). In rhesus monkeys, YM-53601 decreased plasma nonHDL-C by 37% (50 mg kg 71, twice daily for 21 days, P50.01), whereas the HMG-CoA reductase inhibitor, pravastatin, failed to do (25 mg kg 71 , twice daily for 28 days). 4 YM-53601 caused plasma triglyceride reduction in hamsters fed a normal diet (81% decrease at 50 mg kg 71 , daily for 5 days, P50.001). In hamsters fed a high-fat diet, the ability of YM-53601 to lower triglyceride (by 73%, P50.001) was superior to that of feno®brate (by 53%, P50.001), the most potent ®brate (dosage of each drug: 100 mg kg 71, daily for 7 days). 5 This is the ®rst report that a squalene synthase inhibitor is superior to an HMG-CoA reductase inhibitor in lowering plasma nonHDL-C level in rhesus monkeys and is superior to a ®brate in signi®cantly lowering plasma triglyceride level. YM-53601 may therefore prove useful in treating hypercholesterolemia and hypertriglyceridemia in humans.
1 To better understand how it decreases plasma cholesterol and triglyceride levels, we evaluated the effect of (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole monohydrochloride (YM-53601) on lipogenic biosynthesis in the liver and lipid secretion from the liver in rats and hamsters. 2 Single administration of YM-53601 in cholestyramine-treated rats inhibited triglyceride and free fatty acid (FFA) biosynthesis at a similar dose range to that at which it inhibited cholesterol biosynthesis. YM-53601 inhibited both triglyceride and FFA biosynthesis in hamsters treated with cholestyramine. 3 YM-53601 by single oral administration decreased the enhanced plasma triglyceride levels in hamsters induced by an injection of protamine sulfate, which inhibits lipoprotein lipase (LPL) and consequently increases plasma very low-density lipoprotein (VLDL) triglyceride levels. YM-53601 also decreased the enhanced plasma triglyceride and cholesterol levels in hamsters treated with Triton WR1339, which also inhibits the degradation of VLDL. Plasma cholesterol was significantly decreased as soon as 1 h after single administration of YM-53601 in hamsters fed a normal diet. 4 This is the first report that a squalene synthase inhibitor suppresses lipogenic biosynthesis in the liver and cholesterol and triglyceride secretion from the liver in vivo. We therefore suggest that the mechanism by which YM-53601 decreases plasma triglyceride might include these effects. The finding that YM-53601 rapidly decreased plasma cholesterol suggests that this compound may be effective in decreasing plasma cholesterol levels early in the course of treatment of hypercholesterolemia in humans.
The effects of salts on canine taste responses to umami substances were examined by recording the activity of the chorda tympani nerve. 1) The responses to monosodium glutamate (MSG), disodium 5'-guanylate (GMP), and that induced by the synergism between MSG and GMP were enhanced by the presence of various salts. 2) The effective salts were those carrying inorganic cations such as Na, K, and Mg, while CaCl2 had no enhancing effect. Salts carrying organic cations such as tris(hydroxymethyl)aminomethane (Tris), choline, N-methyl-D-glucamine, and 1,3-bis[tris(hydroxymethyl)-methylamino]propane also produced positive results. 3) The dependence of the umami responses on NaCl and MgCl2 concentrations showed a bell-shaped response curve with the maximal enhancing effect being seen at 100 mM NaCl and 3-10 mM MgCl2. 4) The degree of the enhancement depended not only on the species of the cation, but also on that of anion. For example, 100 mM NaCl showed a much larger enhancing effect than Na phosphate, Na2SO4, and Na4Fe(CN)6 at equimolar Na+. 5) The enhancing effects of salts on the responses to the umami substances could not be simply explained in terms of the permeability of cation and anion of salts. It was speculated that the binding of both cations and anions to the receptor membranes leads to changes in the interaction of the umami substances with the receptor proteins.
The aim of this study was to establish an experimental model of the escape phenomenon, in which plasma cholesterol, initially reduced by a 3‐hydroxy‐3‐methylglutaryl CoA (HMG‐CoA) reductase inhibitor such as pravastatin, increases again on long‐term administration. We also evaluated the efficacy of YM‐53601 ((E)‐2‐[2‐fluoro‐2‐ (quinuclidin‐3‐ylidene) ethoxy]‐9H‐carbazole monohydrochloride), a squalene synthase inhibitor, in this model. Pravastatin inhibited cholesterol biosynthesis in hamster primary hepatocytes (IC50, 14 nM). After pre‐treatment with pravastatin, in contrast, almost no effect on cholesterol biosynthesis was seen. In hamsters fed a high fat diet, 3 mg kg−1 pravastatin for 9 days decreased plasma non‐HDL cholesterol (total cholesterol – high density lipoprotein cholesterol) (P<0.01), but this effect was lost between 17 and 27 days of treatment, accompanied by an increase in HMG‐CoA reductase activity. No such increase in plasma non‐HDL cholesterol was seen with YM‐53601 at 30 mg kg−1 after 9 (P<0.001), 17 (P<0.01) or 27 (P<0.001) days of treatment. Replacement of pravastatin with YM‐53601 caused a decrease in plasma non‐HDL cholesterol by 53% (P<0.001) and in HMG‐CoA reductase activity. This animal model thus satisfactorily replicates the escape phenomenon observed in humans and may therefore be useful in evaluation of lipid‐lowering agents, specifically comparison of HMG‐CoA reductase inhibitors. Further, YM‐53601 may be useful in the treatment of hypercholesterolemia without induction of the escape phenomenon. British Journal of Pharmacology (2002) 135, 1572–1578; doi:
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