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Venkata Ramana Murthy Chavali, Naqi Haider, Brent A. Bell, Ying Song, Joshua L Dunaief; Hepatic Lipase C knockout mouse has diminished ERGs and Bruch’s lipid deposits. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1343. doi: https://doi.org/.
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Single nucleotide polymorphisms in the Hepatic lipase C (LIPC) gene were significantly associated with age-related macular degeneration (AMD) in several genome-wide association studies. Expression of Lipc transcripts and protein were predominantly localized to the retinal pigment epithelium (RPE) layer, however its function in the eye remains unknown. The goal of this study is to characterize retinal structure and function in a systemic Lipc-/-knock out mouse.
The Lipc-/-mice (Jackson Labs, Stock# 002056) on a C57BL/6J background were aged for up to 28 months for our studies. The mouse model was verified by genotyping, Lipc transcript expression, and Western analysis of retinal extracts. Retinal phenotype was assessed with respect to normal C57BL/6J mice at 8mo, 12mo, 24mo and 28 months of age using fundoscopy, spectral domain optical coherence tomography and electroretinography (ERG). Light and electron microscopy of the retinal sections along with immunohistochemistry with selected retinal antibodies was performed to determine whether Lipc-/-mice develop retinal pathology with ageing.
The expression of Lipc transcripts and corresponding protein were not detected in the eye tissues of Lipc-/-mice. These mice have increased levels of total plasma cholesterol and high-density lipoprotein (HDL). Fundus imaging did not reveal any gross abnormalities in the Lipc-/-mice up to 12mo of age. In mice over 20 mo of age, small punctate, hyperreflective foci were observed around the optic nerve in Lipc-/-mice when compared to C57BL/6J mice. A significant reduction in Rod-A wave response was observed in the Lipc-/-mice starting at 12mo along with decreased Cone responses as they age. Ultrastructural analysis of Lipc-/-mice at 12 mo revealed the presence of lipid deposits in the sub-RPE and choroidal region throughout the retina.
When compared to normal C57BL/6J mice, the Lipc-/-mice develop age-related retinal changes. It is of interest that eyes from AMD patients also have lipid accumulation in Bruch’s membrane. High levels of plasma HDL-cholesterol have been associated with increased risk for advanced AMD. However, HDL has not been investigated as a major source of drusen lipid, nor has it been suggested in the literature that HDL contributes to drusen deposition in AMD in a substantial manner. Further characterization of our Lipc-/-mouse model will address these critical knowledge gaps.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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