Abstract
Previous studies in our laboratory have provided direct evidence for the existence of distinct cholesterol domains within the plasma membranes of human ocular lens fiber cells. The fiber cell plasma membrane is unique in that it contains unusually high concentrations of cholesterol, with cholesterol to phospholipid (C/P) mole ratios ranging from 1 to 4. Since membrane cholesterol content is disturbed in the development of cataracts, it was hypothesized that perturbation of cholesterol domain structure occurs in cataracts. In this study, fiber cell plasma membranes were isolated from both normal (control) and cataractous lenses and assayed for cholesterol and phospholipid. Control and cataractous whole lens membranes had C/P mole ratios of 3.1 and 1.7, respectively. Small angle x-ray diffraction approaches were used to directly examine the structural organization of the cataractous lens plasma membrane versus control. Both normal and cataractous oriented membranes yielded meridional diffraction peaks corresponding to a unit cell periodicity of 34.0 A, consistent with the presence of immiscible cholesterol domains. However, comparison of diffraction patterns indicated that cataractous lens membranes contained more pronounced and better defined cholesterol domains than controls, over a broad range of temperature (5-40 degrees C) and relative humidity (52-92%) levels. In addition, diffraction analyses of the sterol-poor regions of cataractous membranes indicated increased membrane rigidity as compared with control membranes. Modification of the membrane lipid environment, such as by oxidative insult, is believed to be one potential mechanism for the formation of highly resolved cholesterol domains despite significantly reduced cholesterol content. The results of this x-ray diffraction study provide evidence for fundamental changes in the lens fiber cell plasma membrane structure in cataracts, including the presence of more prominent and highly ordered, immiscible cholesterol domains.
Highlights
The human ocular lens is an optical tissue that contributes to normal visual physiology by providing a means of light refraction and accommodation
Using small angle x-ray diffraction approaches, we recently provided direct evidence that cholesterol is organized into discrete clusters or domains within normal, non-cataractous lens plasma membranes [27]
Data collected in this study suggest that lower levels of cholesterol paradoxically produce more stable domains in cataractous lens membranes
Summary
Cholesterol domains were observed in both native and reconstituted lens membranes and remained stable over a broad range of temperature and relative humidity levels [27]. Immiscible cholesterol monohydrate domains were present in both normal and cataractous whole lens plasma membranes and remained stable over a broad range of temperature and relative humidity conditions. The diffraction peaks corresponding to cholesterol domains in the cataractous lens membranes were more intense as compared with controls, suggesting that membrane-restricted cholesterol domains are a more prominent feature of this disease These results were quite surprising since it was initially hypothesized that the lower C/P mole ratio in the cataractous membranes would yield relatively weaker or smaller cholesterol domains. Modification of the lens membrane by age-related insults, such as oxidative stress, may promote cholesterol domain formation
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