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Michael Landowski, Una L Kelly, Daniel Grigsby, Marybeth Groelle, Catherine Bowes Rickman; Dietary Cholesterol Contributes to Vision Loss in a Complement-Dysregulated AMD Mouse Model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):348. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Variants in complement factor H (CFH), specifically the H402 variant, are associated with increased risk for AMD development, but the molecular basis of the risk-association of CFH variants with AMD is unclear. We have recently shown that aged humanized CFH mice expressing the H402 (CFH-HH:Cfh-/-, H402 mice) variant, but not the normal Y402 (CFH-Y:Cfh-/-, Y402 mice) variant, develop AMD-like pathologies when fed an 8 week high fat, cholesterol-enriched (HFC) diet. Both aged Y402 and H402 mice fed a HFC diet develop fatty liver disease, a consequence of dysregulated hepatic cholesterol homeostasis that is also seen in control C57BL/6J mice fed HFC. We hypothesized aged H402 mice have impaired ocular cholesterol regulation compared to Y402 mice and this contributes to the development of AMD-like pathologies in the H402 mice. We tested this hypothesis by feeding aged H402 mice a high fat but with no added cholesterol (HF) and high cholesterol with no added fat (HC) diet to examine the role of dietary cholesterol in AMD-like pathology development.
H402 mice aged to 90 weeks were continued on a normal diet (ND) or switched to a HFC, HF, or HC diet for 8 weeks. Electroretinograms (ERGs) were recorded. Eyes were collected for histology to assess retinal pathology and for biochemistry. Complement and apolipoprotein levels were measured in the plasma and eye tissue. Mice were also evaluated for the presence of fatty liver disease.
Aged H402 mice fed a HFC or HC diet developed a statistically significant decrease in visual function, detected as a decrease in their scotopic ERG responses compared to age-matched H402 mice fed a ND or HF diet. The decrease in ERG responses correlated with cholesterol-induced systemic changes such as the presence of fatty liver disease and increased plasma ApoE and Clusterin levels. Interestingly, plasma C3/C3b/iC3b and Factor B levels increased similarly in all mice fed a HFC, HF or HC diet compared to ND fed controls.
The presence of dietary cholesterol and its systemic effects correlates with visual dysfunction in H402 mice. Strikingly, complement activation does not correlate with visual dysfunction, suggesting the AMD risk associated with the CFH variants is not due to the canonical role of CFH in complement regulation. Our results suggest targeting cholesterol may be a viable therapeutic strategy in AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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