Specific restriction of cholesterol from cortical lens gap junctional membrane in the U18666A cataract

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Abstract
We have hypothesized that the cholesterol synthesis inhibitor, U18666A, induces nuclear cataracts in the rat by restricting the sterol content of the lens plasma membrane and, therefore, disrupting the structure of gap junctions. In order to directly examine this hypothesis, we isolated total plasma membrane and plasma membrane enriched in gap junctions from the cortical and nuclear regions of lenses from control and U18666A-treated rats. The protein, phospholipid and sterol compositions of the membrane fractions were determined and compared. U18666A treatment resulted in decreased sterol concentrations of both membrane fractions isolated from both the cortical and nuclear regions. The sterol content of total plasma membrane from the cortex and from the nucleus was decreased by 57%, and 36% respectively. The sterol content of the gap junctional membrane (membrane domain enriched in gap junctions) from the cortex and from the nucleus was decreased by 71% and 43% respectively. The observation of a selective decrease in the total sterol content of the cortical gap junctional membrane was reinforced by finding a 50% decrease in the sterol/phospholipid molar ratio of this fraction. The corresponding decrease in the sterol/phospholipid ratio of cortical total plasma membrane was only 22%. The sterol/phospholipid ratio of nuclear total plasma membrane was slightly increased (16%), and the sterol/phospholipid ratio of nuclear gap junctional membrane was decreased by only 8%. These data suggest to us that inhibition of cholesterol synthesis in the rat lens by U18666A results in a specific restriction of cholesterol availability for the synthesis of gap junctional membrane. Alteration of the sterol environment of these plasma membrane organelles may be the first step in the cataractogenesis induced by U18666A.